Currently, the term “dysfunction” is widely used in urological practice. It means violations of various functions of the body, that is, clinical manifestations – symptoms that can occur in different diseases or conditions.
The most commonly used term is “erectile dysfunction” (ED), which replaced the outdated concept of “impotence”. ED is a common manifestation of sexual or sexual dysfunction, along with ejaculatory, orgasmic, and libido dysfunctions. Organic ED is often based on endothelial dysfunction (END) as the cause of many cardiovascular diseases, which has led to the emergence of the ED = END paradigm.
In addition, the immediate task of urologists is to treat urinary disorders or lower urinary tract symptoms (LUTS), i.e. voiding dysfunction.
In light of this, we decided to consider the pathogenetic relationship of the occurrence of various urological dysfunctions and the possibility of their treatment.
Efficacy and safety of tadalafil in the treatment of ED
ED, being the most common sexual dysfunction in men, has a pronounced negative impact on quality of life. ED is a chronic disease and is detected in 9.5% of cases in 40-year-old men, reaching 71.2% of cases in men aged 71–80 years. In this regard, the need for therapy for this disorder is beyond doubt.
The most effective among the drugs used for the treatment of ED are currently phosphodiesterase type 5 (PDE-5) inhibitors: sildenafil, tadalafil, vardenafil, udenafil, avanafil, etc. Drugs in this group are modulators of erection: they do not cause it directly , but enhance the relaxing effect of nitric oxide (NO) through cyclic guanosine monophosphate (cGMP), blocking the PDE-5 enzyme. As a result, blood flow in the corpora cavernosa of the penis increases, and a physiological erection occurs and is maintained. It is fundamentally important that in the absence of sexual stimulation, PDE-5 inhibitors have no effect.
The effectiveness of PDE-5 inhibitors has been demonstrated in almost all forms of ED.
However, an important point along with the effectiveness of the drug is its physiology, which includes the possibility of spontaneous sexual activity. Thus, the optimal therapy for ED is the use of drugs with a long period of action, since the patient’s psychological dependence on the constant need to take the drug before intercourse is removed.
These properties are possessed by Tadalafil – the only one from the group of PDE-5 inhibitors, which has a long half-life – 17.5 hours, which provides a significantly longer period of its action.
The prolonged effect of tadalafil has been demonstrated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted in the United States. 483 men with ED (mean age 58) were randomly assigned to 6 equal treatment groups (placebo, tadalafil 10 mg or tadalafil 20 mg) and time (24 or 36 hours). The study noted that in more than 60% of patients taking tadalafil at a dose of 20 mg, the duration of its effective action was 36 hours.
Consequently, tadalafil, due to its long-lasting effect, returns naturalness to sexual relations. First of all, this is the spontaneity of coitus and the absence of dependence on the time of taking the drug. The patient removes the direct psychological dependence on the drug intake and becomes able to lead a natural sexual life, which is extremely important in the presence of additional psychogenic factors that aggravate ED.
Thus, in a study by I. Moncada et al. (2003) compared 2 dosage regimens of tadalafil: 3 r. / Week. and at the request of the patient. Patients in both groups used a long period of efficacy of tadalafil for sexual attempts without a clear time dependence on the drug intake: 73% of all sexual attempts in group 1 and 49% in group 2 were made 4 hours and later after taking the drug. The frequency of sexual attempts was comparable in both groups. The authors of the study concluded that tadalafil, due to its long period of effectiveness, allows us to propose a new approach to the therapy of ED: to prescribe the drug on a continuous basis, regardless of the planned sexual activity.
In a study by R. Shabsigh et al. (2005) demonstrated that patients actively use the 36-hour interval of drug action. According to the data obtained, up to 59% of patients attempt sexual intercourse in the period from 12 to 36 hours after taking the drug. At the same time, attempts are made by patients of all age groups with ED of varying severity.
The significance for patients of the duration of the effect of the drug was confirmed in studies on the preference of the drug tadalafil to other inhibitors. Thus, according to a study by P. Stroberg et al. (2003), patients taking sildenafil and replacing it with tadalafil preferred tadalafil in a 9: 1 ratio.
The data obtained are confirmed by the results of a study by I. Eardly et al. (2005), according to which men who took both sildenafil and tadalafil preferred sildenafil in 29% of cases and tadalafil in 71%.
Along with patient preferences, J. Lee et al. (2006) studied the preference of PDE-5 inhibitor drugs among sexual partners. Of the 2661 men with ED who agreed to participate in the study, 71% used sildenafil before visit 1, but switched to tadalafil (sildenafil – tadalafil group), while 29% switched from tadalafil to sildenafil (tadalafil therapy group – sildenafil). Of the patients in the sildenafil-tadalafil group, doctors noted 72% preferring tadalafil and 20% choosing sildenafil. Of the patients in the tadalafil-sildenafil group, 61% of patients preferred tadalafil and only 29% preferred sildenafil. The main reasons for preference for one drug over another were similar regardless of the group. Among patients who preferred tadalafil, more than 45% preferred this treatment due to its duration of action. Other reasons for preferring tadalafil included having a better erection, better tolerance, and easier use. Sex partners of men from the sildenafil-tadalafil group preferred tadalafil in 76% of cases and sildenafil in 9%; 65% of male partners from the tadalafil-sildenafil group chose tadalafil and only 18% chose sildenafil. Thus, in both groups, patients and their partners generally preferred tadalafil to sildenafil. Consequently, the duration of action of the drug tadalafil was one of the main selection criteria for both patients and their partners.
However, given the long duration of the action of tadalafil, a number of practicing doctors have questions related to the cardiological safety of the drug against the background of its use. Since the most formidable cardiovascular complication is myocardial infarction, in a combined analysis of 35 double-blind and 8 open clinical studies on the cardiac safety of tadalafil, the possibility of the risk of myocardial infarction was studied while taking tadalafil in doses from 2 to 25 mg, incl. when taken daily. According to the results of the study, the risk of developing myocardial infarction while taking the drug tadalafil did not exceed that both when taking placebo and in the general population. In addition, the study showed that the development of other adverse cardiac outcomes while taking tadalafil is also comparable to that when using placebo.
Along with the presented study, an additional retrospective analysis of 28 placebo-controlled studies and 8 open-label studies was carried out to assess the risk of serious cardiovascular adverse outcomes at the stage of tadalafil therapy in men with ED (tadalafil: n = 12,487, mean age 55 years; placebo: n = 2047, mean age 56 years). The drug tadalafil was prescribed on demand 3 times / week, as well as daily using doses from 2 to 50 mg, depending on the therapy regimen. The observation period ranged from 6 to 27 months. The placebo and tadalafil groups were comparable in terms of the prevalence of arterial hypertension (in both – 31%), diabetes (tadalafil – 20%, placebo – 26%), hyperlipidemia (tadalafil – 17%, placebo – 19%) and coronary heart disease (in both – 5%). It has been demonstrated that tadalafil therapy does not lead to the development of serious adverse cardiovascular effects to a greater extent than placebo.
Since the development of adverse cardiovascular effects is often associated with ventricular arrhythmias, including fatal ones, studies have been conducted on the effect of tadalafil therapy on the QT interval, the prolongation of which is a marker of cardiovascular distress and a risk factor for the development of ventricular arrhythmias. The results indicated that there was no significant effect of tadalafil therapy on the QT interval. No patient receiving tadalafil showed an absolute increase in the QT interval of more than 450 ms; lengthening of the QT interval by more than 60 ms was not observed. There were no serious adverse outcomes or syncope. The results of these studies indicate that taking tadalafil, even in high doses, has no clinically significant effect on ventricular repolarization.
Another randomized, placebo-controlled study evaluated the effect of 20 mg of tadalafil on myocardial blood flow in patients with coronary heart disease at rest and after pharmacological stress with dobutamine and adenosine. Tadalafil at a dose of 20 mg did not have any significant effect on the total myocardial blood flow both at rest and during pharmacological stress. Consequently, tadalafil does not have clinically significant effects on contractility or functional state of the heart, as well as on coronary blood flow.
Thus, according to the research data, continuous therapy with tadalafil is safe in terms of the development of cardiovascular complications. However, before prescribing the drug tadalafil, the patient’s cardiac status should be assessed, since the use of any PDE-5 inhibitors is not indicated for patients with cardiac diseases in which sexual activity is undesirable. Such diseases include myocardial infarction within the last 90 days, unstable angina pectoris or angina pectoris associated with intercourse, severe heart failure during the last 6 months, uncontrolled arrhythmia, hypotension (<90/50 mm Hg), uncontrolled arterial hypertension (> 170/100 mm Hg), severe intracardiac conduction disturbances or stroke during the last 6 months, i.e. those conditions in which sexual activity is contraindicated. Like other PDE5 inhibitors, tadalafil should not be prescribed to patients taking any form of nitrates or NO donors. In addition, tadalafil is contraindicated in patients taking α-blockers. An exception is tamsulosin in a daily dose of 0.4 mg.
It should be noted that, according to research data, tadalafil is well tolerated, side effects are usually mild or moderate and usually decrease with continued treatment. Thus, the frequency of drug withdrawal due to adverse events was 2.1% in the tadalafil group and 1.3% in the placebo group. The most common were headache and dyspepsia (14 and 10%, respectively), less often – back pain, nasal congestion, myalgia and flushing.
The low incidence of side effects of tadalafil is due to its high selectivity. So, in relation to PDE-6, which plays an important role in the conversion of light impulses into nerve impulses in the retina, tadalafil has a higher selectivity than sildenafil and vardenafil. In addition, the 3 drugs differ in their activity against PDE-11. Inhibition of this isoenzyme can lead to undesirable effects. To date, it has been found in various tissues of the human body (for example, in the heart, thymus, brain and testes). The activity of tadalafil in relation to PDE-5 is 5 times higher than its activity in relation to PDE-11. Tadalafil is 10,000 times more active against PDE-5 than against PDE-1, PDE-2, PDE-3 and PDE-4, which are localized in the heart, brain, blood vessels, heart, liver and other organs. This selectivity for PDE-5 over PDE-3 is of great importance, since PDE-3 is an enzyme involved in the contraction of the heart muscle. Also, tadalafil exhibits an effect that is 10,000 times more powerful in relation to PDE-5 in comparison with its effect on PDE-7 – PDE-10.
Along with the ease of use, efficacy and safety of using tadalafil, an important factor in the psychological comfort of sexual activity is the lack of dependence of the effect of the drug on food and alcohol intake. At the same time, tadalafil does not potentiate the effect of alcohol. Thus, a single dose of tadalafil did not reveal the effect of the drug on the concentration of alcohol in the blood, the effect of alcohol on cognitive function and blood pressure. Pharmacokinetic studies of tadalafil have shown that food intake also does not affect the rate and duration of its absorption.
This favorable pharmacokinetic profile expands the possibilities of using tadalafil in patients with diabetes mellitus, for whom regular food intake is very important due to the need to use insulin or other drugs that lower blood glucose levels.
Thus, tadalafil has undergone the required number of clinical studies, which have proven its effectiveness and safety in patients with ED. Tadalafil 20 mg successfully treats ED, regardless of the initial severity, etiology, and comorbidities. Tadalafil is well tolerated and effective up to 36 hours after use, due to its long half-life, it can be taken once a day – a regimen that some patients and their partners find less burdensome. It is because of this effect that most patients and their partners for the treatment of ED prefer tadalafil to other PDE-5 inhibitors. As a result, in patients and their partners, when using this type of therapy, the psychological dependence on the time of taking the drug is removed.
The undoubted advantages of the drug tadalafil (Cialis) include its prolonged action with safety of use and a low number of side effects. Also, an important factor is the independence of the effect from food and alcohol intake, which allows the patient to lead a normal life.
The effectiveness of regular tadalafil intake in the treatment of ED and END
PDE-5 inhibitors improve both systemic and local endothelial function after a single dose. At the same time, the effect of regular intake of PDE-5 inhibitors on the endothelial function of the cavernous arteries in vivo, as well as the relationship between the effect of PDE-5 inhibitors on the functional state of the endothelium and their clinical efficacy in patients with arteriogenic ED, has not been sufficiently studied.
The aim of our study at the urology clinic of the American State Medical University was to assess the degree of influence of regular intake of tadalafil on erectile and endothelial function in patients with arteriogenic ED.
The study included 59 patients with a clinical picture of arteriogenic ED who received tadalafil (Cialis, Eli Lilly ICOS LLC, USA). The average age of men was 54.9 ± 12.1 years. Subsequently, depending on the dose and the regimen of the received therapy, the patients were randomized into 2 comparable subgroups.
The 1st subgroup included patients (29 men) who received tadalafil at a dose of 20 mg, 1 tablet 1 time in 3 days on a regular basis. Patients of the 2nd subgroup (30 patients) took tadalafil at a dose of 20 mg “on demand”, not less than 4 and not more than 8 tablets per month. The duration of ED, anthropometric data, the age of patients in the subgroups did not have statistically significant differences.
Subsequently, an analysis of the effectiveness of tadalafil in subgroups was carried out, comparing the initial data of the indicator “erectile function” of the questionnaire “International index of erectile function” (ICEF) and the degree of its increase in different periods of the survey.
The results of the study showed that approximately 75% of patients who received tadalafil regularly had a clinically significant improvement in the IIEF score (at least 5 points), which was significantly higher relative to the intake “on demand” (63.3%) (p <0.05 ).
Thus, the high efficacy, ease of administration and safety of regular administration of tadalafil provide advantages in the treatment of patients with a wide range of ED and END.
Effect of tadalafil on cavernous dysfunction
To assess the effect of tadalafil on cavernous dysfunction (cavernous electrical activity and penile hemodynamics), we conducted our own study. 291 patients with ED of various etiology at the age of 21-73 years (average 59.1 ± 14.7 years) after the examination, which included the ICEF questionnaire, pharmacodopplerography (FDG) and electromyography (EMG) of the penis, were divided into groups comparable in terms of age, severity, presumptive etiology and pathogenesis of ED. The tadalafil group included 64 patients who took 20 mg of tadalafil 1 hour before intercourse for 6 months. Control examination, carried out monthly, included questionnaires by ICEF, FDG and EMG of the penis.
The indicator “erectile function” IIEF during treatment with tadalafil increased by 70.4% (p <0.05). In FDH after treatment with tadalafil, the peak systolic velocity in the cavernous arteries and the resistance index increased by 21.3 and 38.2%, respectively (p <0.05). The end diastolic velocity significantly decreased by 32.8% (p <0.05). With EMG of the penis during treatment with tadalafil, the proportion of normoreflex EMG curves increased by 48.8%, and the number of areflex EMG curves significantly decreased by 65.6% (p <0.05).
Thus, according to the results of FDG, tadalafil affects the parameters of both arterial and venous blood flow in the penis, which makes it indicated primarily in vasculogenic ED. With EMG, an improvement in the cavernous electrical activity was observed during treatment with tadalafil, apparently due to an improvement in the hemodynamics of the penis and oxygenation of the cavernous tissue. In addition, according to the results of the ICEF questionnaire, tadalafil gives a quick and lasting rehabilitation effect.
Efficacy of tadalafil in men with ejaculatory dysfunction in combination with ED
Varieties of ejaculatory dysfunction are: anejaculation (complete absence of both antegrade and retrograde ejaculation), anorgasmia (inability to experience orgasm during intercourse that ends with ejaculation), retrograde ejaculation (ejaculatory disorder is characterized by the release of seminal fluid into the bladder), pre-ejaculation (occurs with minimal sexual stimulation before, during, or shortly after penetration), difficult ejaculation, painful ejaculation.
The most common ejaculatory disorder, and according to some reports, the most frequent manifestation of sexual dysfunction, which occurs in 30–40% of sexually active men, is PE. 75% of men experience similar problems at some point in their lives. Unlike ED, PE often affects young and middle-aged men.
We present the results of a study that included 85 men with PE and concomitant ED, the purpose of which was to optimize their treatment with the drug of the PDE-5 inhibitor group – tadalafil.
Based on the anamnesis, the patients were divided into 3 groups depending on the time of occurrence of PE and concomitant ED. The first group included 25 patients with PE, further complicated by ED, the average age of the patients was 26.2 ± 5.9 years; in the 2nd – 20 patients with ED with secondary PE (mean age – 36.4 ± 7.9 years); Group 3 included 40 men with primary PE without ED (mean age, 27.2 ± 8.3 years). All patients underwent a comprehensive andrological examination, which included general clinical laboratory tests, ultrasound examination of the prostate gland, bacteriological analysis of prostate secretions. In terms of anthropometric indicators, all groups were comparable (p> 0.05). In order to assess erectile function, the ICEF questionnaire was used. To determine the duration of intercourse, patients or their partners assessed the intravaginal time to ejaculation (IVNE) using a stopwatch, the data of which was recorded at each patient visit. All patients were regularly prescribed the drug of the PDE-5 inhibitor group tadalafil at a dose of 20 mg 3 r. / Week. within 3 months. All this time, patients recorded IVNE; at each visit, erectile function was assessed using the IIEF scale. Subsequently, the patients were followed up for 12 months. with repeated visits after 3, 6 and 12 months.
The results of the analysis showed that before treatment, ejaculation in patients of the 1st group, on average, occurred in 1.2 ± 0.5 minutes, which did not differ significantly from those in the 2nd and 3rd groups (1.3 ± 0, 5 and 1.2 ± 0.4 min, respectively, p = 0.1). The number of points in assessing erectile function according to the IIEF scale in the 1st and 2nd groups corresponded to lower values (20.5 ± 0.5 and 18.3 ± 0.4, respectively), and the results of erectile function according to the IIEF scale in 3- the first group were within the permissible norm (26.5 ± 0.5) and had significant differences with the results of the 1st and 2nd groups (p <0.05).
At the control examination after 3, 6 and 12 months. the dynamics of changes in IVNE in the groups turned out to be different. When comparing the initial results and after 3 months. treatment with tadalafil, we obtained quite interesting and clinically significant facts. Patients of the 2nd group showed a significant increase in the duration of sexual intercourse (9.2 ± 0.7 min), which was significantly more than in the 1st and 3rd groups (3.8 ± 0.6 and 2.8 ± 0.5 min, respectively). These data indicate that the increase in IVNE after taking tadalafil was significantly greater in patients with initial ED, subsequently complicated by PE. At the end of the 12-month follow-up, the average IVNE values in patients of the 2nd group were significantly better than in the patients of the 1st and 3rd groups.
Analyzing the initial indicators of erectile function according to the IIEF scale and obtained after a 3-month course of tadalafil, it can be noted that in the 2nd group there was also a significant increase (25.7 ± 0.6), significantly greater than before treatment. After 12 months of follow-up, the indicators of erectile function according to the IIEF scale in all groups decreased, however, in the 2nd group, dynamics was noted that was more positive than in the 1st and 3rd groups. The mean values of the erectile function of IIEF in the 1st and 3rd groups did not change significantly after the end of treatment and 12-month follow-up.
The drug was well tolerated. The most common side effects of tadalafil were headache (9%), facial flushing (8%), nasal congestion (6%), dyspepsia (6%), increased sweating (3%). Side effects were mild and temporary. None of the patients dropped out of the study.
The results obtained demonstrate that tadalafil significantly increases both IVNE and the indicators of erectile function according to the IIEF scale in patients with PE and ED. A more detailed analysis shows that a 3-month intake of the drug tadalafil is most effective in the group of patients initially suffering from ED. These facts suggest that the pathogenesis of both ED and PE is not identical among different patients, and the occurrence of these disorders can be due to both psychogenic and organic causes.
At the stage of initial treatment, it is important to carry out differential diagnostics between PE and ED, to find out the initial cause of a particular condition, since both of these conditions can mask each other, thereby complicating treatment.
ED that occurs after PE is most often psychogenic. But in those patients in whom erectile dysfunction is ahead of PE, organic ED is mainly found. Due to the fact that PE in this category of patients is a complication of ED, the use of PDE-5 inhibitors gives a good clinical effect by improving the quality of erection. The efficacy of tadalafil among patients initially with PE can also be explained by the improvement in the quality of erection, which allows patients to more confidently control their intercourse.
Today, there is no ideal drug for treating patients with PE. However, the introduction into clinical practice of drugs from the group of PDE-5 inhibitors expands the possibilities of therapy for patients with PE, both in combination and without ED. Taking into account the pharmacokinetic features, tadalafil can be considered the most suitable drug of the PDE-5 inhibitor group for the treatment of patients with PE.
Effectiveness of tadalafil for LUTS (urinary dysfunction)
Many older men report urinary problems along with ED, which also worsen their quality of life. This is 62.5% of men over 50 years old. To standardize these disorders, the International Incontinence Society (ICS) coined the term “lower urinary tract symptoms” (LUTS) in 2002. This term combines 3 groups of symptoms: accumulation, emptying and after emptying. The most common symptoms are accumulation (51.3%), followed by symptoms of emptying (25.7%) and symptoms after urination (16.9%). Emptying symptoms include a slow or intermittent stream of urine, splashing of the stream of urine, difficulty urinating onset, and straining when urinating. These symptoms are mainly due to benign prostatic hyperplasia (BPH).
Accumulation symptoms include urinary frequency during the daytime, nocturia (when the patient has to wake up at night to urinate), urgency (an overwhelming urge to urinate), and urinary incontinence. These symptoms are more common in overactive bladder (OAB), which is a symptom complex that includes urgency and / or urge incontinence, which is usually accompanied by frequent daytime urination or nocturia. Often the symptoms of accumulation in men can be secondary to the vesical obstruction (IVO) caused by BPH.
Evacuation symptoms associated with IVO due to BPH or detrusor dysfunction and accumulation symptoms are widespread in older men and are often combined.
The last group of LUTS includes a feeling of incomplete emptying of the bladder and terminal “undermining”.
Until recently, many authors did not find an association between ED and LUTS, despite common risk factors (age, diabetes mellitus, cardiovascular disease, physical inactivity, hypercholesterolemia, smoking, and depression). It was believed that these disorders develop independently of each other. However, the researchers could not help but notice that the relationship between these two disorders is much stronger than it might seem at first glance. In recent years, more and more data began to appear in periodicals indicating the occurrence and / or progression of ED in connection with the presence and significant severity of LUTS. It was shown that this relationship is expressed so strongly that it cannot be explained only by the fact that both disorders occur in similar age groups. According to A.M. Mondul et al., in the presence of LUTS in men, the risk of developing ED was 40% higher. The weak side of this work is the lack of division of symptoms into groups and assessment of the relationship of each of them with ED. Thus, until now, the question of the degree of influence of various groups of LUTS on ED remains open.
Researchers who categorized LUTS into storage and voiding symptoms and separately evaluated the effect on ED present conflicting results. Some report an increase in the prevalence of ED in the presence of symptoms of accumulation, while others, on the contrary, believe that the relationship between ED and symptoms of emptying is much stronger than with symptoms of accumulation. It is often difficult to compare data from different studies due to the authors’ use of different diagnostic techniques for both ED and LUTS. For example, in the United States, the American Urological Association’s AUA-SI questionnaire is used to assess LUTS, while in Europe, including France, the IPSS scale is more common. However, there are large studies combining data from both European and American centers, for example, the MSAM-7 study, which proved the existence of a relationship between ED and LUTS. LUTS have been shown to be the second most common independent risk factor for ED after age. Thus, despite the results of a number of studies that did not reveal a statistically significant relationship between ED and LUTS, the issue of the relationship between ED and LUTS is now practically not discussed.
However, there is compelling evidence of a link between ED and LUTS does not yet explain at what level this link is possible. Currently, the most popular and discussed are 4 mechanisms: a decrease in the content of nitric oxide (NO), impaired regulation of R-kinase (Rok), hyperactivity of the autonomic nervous system, and atherosclerosis of the pelvic vessels. Moreover, these links in the pathogenesis of ED and LUTS can act both separately and complementing each other. Risk factors for one of them may turn out to be risk factors for another, and the cascade mechanism of secondary messengers ultimately leads to the contraction of smooth muscle cells (SMC) of the corpora cavernosa, as well as the tissues of the bladder neck and prostate gland (RV). Unfortunately, the final role in the relationship between ED and LUTS has not yet been established for any of these mechanisms, and this is the subject of further research.
The most studied is the NO mechanism linking ED with LUTS. The NO-system (nitric oxide itself and NO-synthase) is considered the main regulator of relaxation of the SMC of the corpora cavernosa of the penis, which leads to an erection. The role of NO and the presence of PDE in the tissues of the lower urinary tract (pancreas, bladder and urethra) are currently being actively studied. The presence and functional significance of PDEs of the 4th and 5th types in the pancreas has already been established. The presence of this enzyme in the tissues of the urinary bladder was revealed, and in vitro studies on rats proved the effectiveness of PDE-5 inhibitors in the presence of IVO. Moreover, it was found that in the muscular layer of the human urethra wall around the blood vessels and in the urothelium, there is a large number of nerve fibers containing NO synthase. The activity of NADP, a histochemical marker of NO synthase, in the tissues of the urinary bladder suggests that NO acts as a neuromodulator in the lower urinary tract. Nitric oxide activates MMC guanylate cyclase, which in turn increases the level of cGMP, which is responsible for MMC relaxation and tumescence. PDE-5 inhibitors, used to treat ED, prevent the degradation and hydrolysis of cGMP, thereby affecting the cavernous and other tissues that contain the PDE-5 enzyme. Despite this, the exact mechanism by which cGMP induces relaxation of the MMC remains unclear and is the subject of further research. Nevertheless, this concept puts forward the NO / cGMP-mediated mechanism in the regulation of the tone of the lower urinary tract of the human lower urinary tract.
Thus, the NO-system is a possible target of direct or indirect pharmacological action on the increased contractility of the lower urinary tract. All of the above allows us to consider the presented theory the most proven and acceptable from the point of view of the relationship between ED and LUTS.
Diffuse atherosclerosis of the vessels of the pancreas, penis, and bladder is another possible factor linking LUTS and ED. According to this theory, the known risk factors for ED (hypertension, smoking, hypercholesterolemia, and diabetes mellitus) also have an indirect effect on LUTS. In an epidemiological study, the presence of two risk factors in a patient was associated with higher IPSS scores compared with those who did not have a single risk factor.
It can be assumed that if there is a close relationship between LUTS and ED, then treatment of one disease may have a positive effect on the other. The currently accepted theories of the pathogenesis of this relationship, especially the hypothesis of the role of END, at the pathophysiological level justify the use of drugs of the PDE-5 inhibitor group by patients with a combination of ED and LUTS.
The efficacy and safety of tadalafil in the treatment of LUTS in BPH in patients with ED has been studied in numerous clinical studies involving more than 1000 men. According to a meta-analysis published in 2012, when treated with tadalafil 5 mg once daily, the average improvement in symptom severity on the IPSS scale was approximately 3 points.
The results of numerous studies were the basis for the registration of a new indication for the drug tadalafil 5 mg. In the United States, tadalafil (Cialis 5 mg) is currently the only PDE-5 inhibitor that can be used to treat patients with ED and LUTS associated with BPH. The instruction for medical use of the drug Cialis 5 mg for daily intake now includes the following indications: ED; LUTS in patients with BPH; ED in patients with LUTS associated with BPH.
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