Tadalafil-SZ, 28 pcs., 5 mg, film-coated tablets

Tadalafil-SZ, 28 pcs., 5 mg, film-coated tablets

Effect of other drugs on tadalafil

Tadalafil is mainly metabolized with the participation of the CYP3A4 isoenzyme. A selective inhibitor of the CYP3A4 isoenzyme ketoconazole (400 mg/day) increases the exposure of a single dose of tadalafil (AUC) by 312% and Cmax by 22%, and ketoconazole (200 mg/day) increases the exposure of a single dose of tadalafil (AUC) by 107% and Cmax by 107% and Cmax by 22%. 15% relative to AUC and Cmax values ​​for tadalafil alone.

Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increases single-dose tadalafil exposure (AUC) by 124% without changing Cmax. Although specific interactions have not been studied, it can be assumed that other HIV protease inhibitors, such as saquinavir, as well as CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole and grapefruit juice, may increase tadalafil plasma concentrations. The role of transporters (including P-gp) in the distribution of tadalafil is unknown. The potential for drug interactions mediated by transporter inhibition exists.

A selective inducer of the CYP3A4 isoenzyme, rifampicin (at a dose of 600 mg/day), reduces single-dose tadalafil exposure (AUC) by 88% and Cmax by 46% relative to AUC and Cmax for tadalafil alone. It can be assumed that the simultaneous use of other inducers of the CYP3A4 isoenzyme (such as phenobarbital, phenytoin or carbamazepine) should also reduce tadalafil plasma concentrations.

Concomitant use of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without changing the AUC of tadalafil.

An increase in gastric pH as a result of taking the H2-histamine receptor blocker nizatidine had no effect on the pharmacokinetics of tadalafil.

The safety and effectiveness of combining tadalafil with other treatments for erectile dysfunction or other PDE5 inhibitors has not been studied and the use of such combinations is not recommended.

Effect of tadalafil on other drugs

Tadalafil is known to enhance the hypotensive effect of nitrates. This occurs as a result of the additive effect of nitrates and tadalafil on the metabolism of nitric oxide (II) and cGMP. Therefore, the use of tadalafil while taking nitrates is contraindicated.

Tadalafil does not have a clinically significant effect on the clearance of drugs whose metabolism occurs with the participation of cytochrome P450.

Studies have confirmed that tadalafil does not inhibit or induce the isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1.

Tadalafil does not have a clinically significant effect on the AUC of S- or R-warfarin. Tadalafil does not affect the effect of warfarin on PT.

Tadalafil does not potentiate the increase in the duration of bleeding caused by taking acetylsalicylic acid.

Tadalafil has systemic vasodilatory properties and may enhance the effect of antihypertensive drugs. Additionally, patients taking multiple antihypertensive agents and whose hypertension was poorly controlled experienced a slightly greater reduction in blood pressure. In the vast majority of patients, this decrease was not associated with hypotensive symptoms. Patients treated with antihypertensive drugs and taking tadalafil should be given appropriate clinical advice.

There was no significant reduction in blood pressure when healthy volunteers co-administered tadalafil and the selective alpha1A-blocker tamsulosin.

Concomitant use of tadalafil with doxazosin is contraindicated. When tadalafil was administered to healthy volunteers taking doxazosin (4–8 mg/day), an alpha1-blocker, an increase in the hypotensive effect of doxazosin was observed. Some patients experienced symptoms associated with decreased blood pressure, including syncope.

Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated because Riociguat enhances the hypotensive effect of PDE-5 inhibitors.

Drug interaction studies have not been conducted with tadalafil and 5-alpha reductase inhibitors; caution should be exercised when taking them simultaneously.

Tadalafil causes an increase in the bioavailability of ethinyl estradiol when taken orally. A similar increase in bioavailability can be expected with terbutaline, but the clinical implications have not been established.

Tadalafil did not affect the concentration of alcohol, nor did alcohol affect the concentration of tadalafil. At high doses of alcohol (0.7 g/kg), taking tadalafil did not cause a statistically significant decrease in mean blood pressure. Postural dizziness and orthostatic hypotension have been observed in some patients. When taking tadalafil in combination with lower doses of alcohol (0.6 g/kg), no decrease in blood pressure was observed, and dizziness occurred with the same frequency as when taking alcohol alone.

Tadalafil does not have a clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.

Tadalafil

pharmachologic effect

The drug for the treatment of erectile dysfunction is a reversible selective inhibitor of the specific PDE5 cGMP. When sexual arousal causes local release of nitric oxide, inhibition of PDE5 by tadalafil results in increased cGMP levels in the corpus cavernosum of the penis. The consequence of this is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Tadalafil is ineffective in the absence of sexual stimulation.

In vitro studies have shown that tadalafil is a selective PDE5 inhibitor. PDE5 is an enzyme found in the smooth muscles of the corpus cavernosum, in the smooth muscles of the vessels of internal organs, in skeletal muscles, platelets, kidneys, lungs, and cerebellum.

The effect of tadalafil on PDE5 is more active than on other phosphodiesterases. Tadalafil is 10,000 times more active against PDE5 than against PDE1, PDE2, PDE4, which are localized in the heart, brain, blood vessels, liver and other organs. Tadalafil is 10,000 times more potent at blocking PDE5 than PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac muscle contraction. In addition, tadalafil is approximately 700 times more active against PDE5 than against PDE6, which is found in the retina and is responsible for phototransmission. Tadalafil is also 10,000 times more active against PDE5 compared to its effect on PDE7-PDE10.

Effective for 36 hours. The effect appears within 16 minutes after ingestion in the presence of sexual arousal.

Tadalafil in healthy individuals does not cause significant changes in systolic and diastolic blood pressure, compared with placebo, in the supine position (average maximum decrease is 1.6/0.8 mmHg, respectively) and standing (average maximum decrease is 0.2/4.6 mmHg. respectively). Tadalafil does not cause a significant change in heart rate.

Tadalafil does not cause changes in color recognition (blue/green), which is explained by its low affinity for PDE6. In addition, there was no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.

There were no clinically significant effects on sperm characteristics in men taking tadalafil in daily doses for 6 months.

On-demand use of tadalafil for erectile dysfunction in special categories of patients

S.I. Gamidov1, 2, T.V. Shatylko3, N.G. Hasanov1, N.A. Naumov1

1 Federal State Budgetary Institution Scientific Center for Obstetrics, Gynecology and Perinatology named after. IN AND. Kulakov" of the Ministry of Health of Russia; Russia, 117997 Moscow, st. Academician Oparina, 4; 2 Federal State Autonomous Educational Institution of Higher Education First Moscow State Medical University named after. THEM. Sechenov Ministry of Health of Russia; Russia, 119991 Moscow, st. Bolshaya Pirogovskaya, 2, building 4; 3 Federal State Budgetary Educational Institution of Higher Education “Saratov State Medical University named after. IN AND. Razumovsky" of the Ministry of Health of Russia; Russia, 410012 Saratov, st. Bolshaya Kazachya, 112 Contacts: Taras Valerievich Shatylko

Introduction

Erectile dysfunction (ED) is one of the most common and widely discussed types of sexual dysfunction in men. Worldwide, 5–20% of men have moderate or severe ED [1]. The prevalence of ED is constantly increasing, and by 2025, according to projections, 322 million men will suffer from this disorder [2]. Despite the fact that ED as such does not affect life expectancy, it significantly worsens the quality of life not only for the patient himself, but also for his partner.

Currently, there are several treatment strategies for ED, which involve non-invasive and invasive methods. According to the recommendations of the European Association of Urology, the 1st line of therapy includes oral administration of phosphodiesterase type 5 inhibitors (PDE-5) [3]. From a chemical point of view, the IPDE-5 molecules are similar in structure to cyclic guanosine monophosphate. Therefore, they can competitively bind to phosphodiesterase and suppress the hydrolysis of guanosine monophosphate, which facilitates the development of erection [4]. Currently, a large number of drugs of the PDE-5 class are proposed, although not all of them have undergone clinical trials and have been approved by the relevant regulatory authorities. Thus, in Russia, drugs are available based on one of 4 active ingredients: sildenafil, tadalafil, vardenafil and udenafil. Their effectiveness and safety are comparable; some unprincipled differences are noted in the structure of adverse events during use [5–7].

Meta-analysis by L. Chen et al. in 2015, showed that sildenafil is characterized by the highest effectiveness and the highest frequency of adverse events, and tadalafil is characterized by average effectiveness and the minimum frequency of adverse events [8]. However, these data require revision, since the meta-analysis included all studies on these drugs. B. Gong et al. conducted a more statistically rigorous meta-analysis, including only those studies that directly compared sildenafil and tadalafil [9]. It turned out that their effectiveness is approximately the same, but patients and their partners prefer tadalafil because of its ease of administration.

An important factor when choosing a drug is its pharmacokinetics. Tadalafil is a selective long-acting PDE-5 inhibitor. Tadalafil should be taken at least 16 minutes before intended sexual intercourse. The half-life of tadalafil in healthy men is 17.5 hours, and it is this pharmacokinetic parameter that makes tadalafil attractive for the symptomatic treatment of ED. Due to its long half-life, it has the longest duration of action of any PDE-5 inhibitor, which can be up to 36 hours. The patient can attempt sexual activity at any time within 36 hours after taking the drug to determine the optimal time for response development. About 52% of patients with severe ED can successfully have sexual intercourse within 30 minutes after taking tadalafil at a standard dose [10]1.

Probably, thanks to these qualities, in the near future, tadalafil will be able to occupy the niche of the main IPDE-5 for the treatment of ED. Drugs based on it entered the market in 2003.

However, it would be wrong to assume that any one drug can be equally suitable for all patients with ED, especially considering the polyetiology and heterogeneity of this syndrome. This article is devoted to the use of tadalafil in special categories of patients with ED.

Tadalafil in patients with metabolic syndrome

There are several different definitions of metabolic syndrome, but they all include 4 features: abdominal obesity, hypertension, dyslipidemia and carbohydrate metabolism disorders. In the absence of therapy and lifestyle correction, impaired glucose tolerance can develop into type II diabetes mellitus. Treatment of ED in patients with diabetes mellitus is not an easy task due to the combination of vasculogenic and neurogenic components of the pathogenesis of ED, as well as the need to take into account the associated cardiovascular risks and the interaction of prescribed drugs with hypoglycemic agents. Despite this, on-demand tadalafil therapy was effective in patients with diabetes mellitus. We note that the effect on lower urinary tract symptoms (LUTS) in these patients was greater with 5 mg tadalafil daily, although this is not the purpose of this article. Interestingly, tadalafil also improved ejaculatory function in patients with diabetes [11]. There are indications that tadalafil reduced fat-to-muscle ratio and waist circumference in men; Presumably, this occurs due to improved insulin secretion, an increase in the number of androgen receptors and inhibition of testosterone aromatization. In addition, an improvement in endothelial function has been confirmed using the Endo-Pat2000 device [12]. Molecular cellular study by E. Maneschi et al. demonstrated that tadalafil influenced the differentiation of preadipocytes and promoted a healthy phenotype by enhancing the expression of genes characteristic of brown adipose tissue, improving mitochondrial structure and normalizing insulin sensitivity in animal models [13].

In addition, metabolic syndrome may be associated with hypogonadism. A significant decrease in testosterone levels in the blood serum can weaken libido, and this turns out to be an additional pathogenetic factor in the development of ED in metabolic syndrome. There is a hypothesis according to which a regular rhythm of sexual activity helps to normalize the level of endogenous testosterone. In a study by L. Ozcan et al. Long-term use of tadalafil increased testosterone levels in patients with ED and metabolic syndrome without hormone replacement therapy [14]. L. Maresca et al. showed that taking tadalafil and regular exercise enhanced each other's effect in patients with ED and metabolic syndrome [15].

Tadalafil in patients with chronic prostatitis or benign prostatic hyperplasia

In 2007, SJ Grimsley et al. suggested that PDE-5 may mediate relaxation of the smooth muscle of the prostate ducts, facilitating the outflow of their contents, including those that initially entered the acini due to urethral-prostatic reflux [16]. M. Kurita et al. found that PDE-5 inhibitors, in particular tadalafil, relieve chronic pelvic pain [17]. Clinically, these results were confirmed in the work of Y. Nishino et al., who examined patients with benign prostatic hyperplasia (BPH), combined with chronic pelvic pain syndrome [18]. However, the above-described effects of taking tadalafil have not yet been widely confirmed and require further study [19]. P.V. Glybochko et al. demonstrated that PDE-5 increases blood flow not only in the arteries of the penis, but also in the prostate gland [20]. This direction is considered particularly promising, since chronic prostatitis can indirectly cause the development of various sexual dysfunctions [21].

We will not touch upon the issue of daily use of tadalafil for LUTS associated with BPH, as we believe that this issue deserves a separate comprehensive discussion. However, it is known that some men with prostate adenoma can obtain a positive clinical effect from taking PDE-5 on demand [22]. In particular, this applies to patients at high risk of progression of BPH who are prescribed 5-alpha reductase inhibitors (finasteride and dutasteride). These are drugs that can reduce the volume of the prostate gland with long-term use and reduce the risk of developing acute urinary retention in older men. The mechanism of action of these drugs is to inhibit the conversion of testosterone to the active metabolite dihydrotestosterone. It is the influence on testosterone metabolism that is often explained by the characteristic adverse events associated with taking finasteride and dutasteride - the appearance of persistent ED, decreased libido and impaired ejaculation. Several studies have confirmed that tadalafil, taken on demand at a dose of 20 mg, is effective against ED in patients taking dutasteride [23, 24].

Data on the effect on erection of another class of drugs actively used for BPH, namely selective alpha-1a blockers (tamsulosin and silodosin), are contradictory. There is a controversial opinion that they have little positive effect on erectile function. In any case, there is no convincing data on the negative effects of tamsulosin and silodosin on erectile function. Consequently, the question arises about their compatibility with IPDE-5, since both classes of drugs, to one degree or another, affect the tone of the vascular walls. Studies have confirmed the safety and good tolerability of combination therapy for LUTS with tamsulosin and tadalafil, which did not increase the risk of orthostatic collapse [25, 26]. The safety and effectiveness of the combination of tadalafil with silodosin has also been proven [27].

Tadalafil for neurogenic erectile dysfunction

Neurogenic ED is the most difficult form of ED to treat conservatively. The reason is that PDE-5, included in the 1st line of therapy, causes relaxation of the smooth muscles of the cavernous bodies as a result of the accumulation of cyclic guanosine monophosphate, formed due to the action of nitric oxide (NO). If the release of nitric oxide from the nitrergic synapses of parasympathetic nerve fibers does not occur, then IPDE-5 essentially has no point of application and is obviously ineffective. Therefore, for severe types of neurogenic ED, intracavernous injections remain the only effective method of conservative treatment [1]. Nevertheless, with at least partial preservation of the innervation of the penis, IPDE-5 have a certain effectiveness, which can be explained by their ability to biochemically amplify a weak NO signal and activate endothelial NO synthase. Thus, sildenafil, tadalafil and vardenafil are effective in some patients with traumatic spinal cord injury [28], the use of other PDE-5 inhibitors in this category of patients has not been studied.

The pathogenesis of ED and concomitant sexual disorders in multiple sclerosis is very complex [29]. The effectiveness of tadalafil in multiple sclerosis has been demonstrated in several studies. G. Lombardi et al. reported good results with on-demand tadalafil 10 mg in men with ED and multiple sclerosis [30]. 1 patient developed headache during therapy, 1 patient developed tachycardia; These are expected side effects that also occur in people without neurological diseases.

Not a single case of autonomic dysregulation was reliably recorded. In a study by D. Francomano et al. The effect of tadalafil not only on erection, but also on the severity of LUTS, which often occurs in patients with multiple sclerosis, has been confirmed [31]. This study also found a change in the ratio of serum testosterone to estradiol levels with tadalafil.

The use of IPDE-5 may be effective in patients with ED due to Parkinson's disease. In patients with other pathologies of the central nervous system, the use of IPDE-5 is limited due to a possible decrease in libido, the development of endocrine disorders with damage to the hypothalamic-pituitary region, and the potential effect of drugs on the neurological status [32].

The use of tadalafil to regulate reproductive function

One of the debatable questions is how justified is the prescription of IPDE-5 to men with ED who are trying to conceive a child. On the one hand, erection is the most important component of the copulatory cycle, and without it natural conception is almost impossible. On the other hand, some experts express an opinion about the potential testicular and spermatological toxicity of IPDE-5.

Non-specific PDE inhibitors such as caffeine, pentoxifylline and theophylline are known to stimulate sperm motility in vitro. Moreover, pentoxifylline is widely used for this purpose as part of assisted reproductive technologies. The effect of these compounds on male fertility in vivo has not been proven [33].

In a study by Y. Yang et al. The effect of tadalafil on sperm motility and acrosome reaction was assessed [34]. Neither in vitro nor in vivo, tadalafil suppressed gamete motility or increased the incidence of premature acrosome activation. However, this study assessed only the immediate period after the introduction of tadalafil into the medium or after its oral administration, and therefore its results do not allow us to exclude late cumulative toxicity.

Attempts have been made to prove the positive effect of IPDE-5 on spermatogenesis. Thus, in a study by A. Corvasce et al. After 12 weeks of taking tadalafil, spermogram parameters in patients with psychogenic ED significantly improved [35], including an increase in ejaculate volume. This fact indicates that the positive effect on sperm parameters could be caused primarily by the normalization of ejaculation. As is known, phosphodiesterase type 5 is expressed in all muscle tissues of the male reproductive tract, which means that influencing the level of this enzyme makes it possible to pharmacologically regulate ejaculatory function [33].

Conclusion

The effectiveness of tadalafil depends on the etiology of ED, the presence of concomitant diseases and the nature of the therapy. Tadalafil can be used in men with diabetes and metabolic syndrome, as it has been shown to be effective in these groups of patients with ED. Tadalafil combines well with typical medications used for BPH. Tadalafil is effective in some cases for neurogenic ED, although with some limitations; Its most promising use is in spinal cord injury and multiple sclerosis. Convincing data indicating a negative effect of tadalafil on fertility has not been published, although it is also premature to draw a conclusion about its positive effect on spermatogenesis and sperm motility.

Undoubtedly, tadalafil at a dosage of 5 mg for daily use has the greatest potential among all the PDE-5 inhibitors on the market, which made penile rehabilitation after treatment for prostate cancer and single-component therapy for ED and LUTS possible. However, taking tadalafil on demand is acceptable and convenient for many men suffering from ED.

The appearance on the Russian market of a generic tadalafil – “Dynamico Long”, produced on the basis of an Israeli substance2 in compliance with modern requirements and quality standards3, may make this treatment option more accessible4 compared to the use of the original tadalafil. It is important that such treatment has a positive effect not only on erectile, but also on orgasmic and ejaculatory functions, and the long duration of the drug helps maintain spontaneity of sexual life and increases a man’s self-confidence [36, 37].

Literature

1. Hatzimouratidis K., Amar E., Eardley I. et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010;57(5):804–14. DOI: 10.1016/j.eururo.2010.02.020. PMID: 20189712.
2. Ayta IA, McKinlay JB, Krane RJ The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84(1):50–6. DOI: 10.1046/j.1464-410x.1999.00142.x. PMID: 10444124.
3. Ventimiglia E., Capogrosso P., Montorsi F. et al. The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction. Expert Opin Drug Saf 2016;15(2):141–52. DOI: 10.1517/14740338.2016.1131818. PMID: 26752541.
4. Bruzziches R., Francomano D., Gareri P. et al. An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother 2013;14(10):1333– 44. DOI: 10.1517/14656566.2013.799665. PMID: 23675780.
5. Patel CK, Bennett N. Advances in the treatment of erectile dysfunction: what's new and upcoming? F1000Res 2016;5:369–75. DOI: 10.12688/f1000research.7885.1. PMID: 27516878.
6. Rasner P.I., Pushkar D.Yu. Erectile dysfunction – different solutions to the same problem, or Reflections on a given topic. Medical Council 2014;(19):64–71. .
7. Gamidov S.I., Ovchinnikov R.I., Popova A.Yu. et al. Phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction: past, present and future. Urology 2017;(1):103–7. [Gamidov SI, Ovchinnikov RI, Popova AY, Izhbaev SK Phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction: past, present and future. Urologiya = Urology 2017;(1):103–7. (In Russ.)]. DOI: 10.18565/urol.2017.l.103-107. PMID: 28394532.
8. Chen L., Staubli SE, Schneider MP et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol 2015;68(4):674–80. DOI: 10.1016/j.eururo.2015.03.031. PMID: 25817916.
9. Gong B., Ma M., Xie W. et al. Direct comparison of tadalafil with sildenafil for the treatment of erectile dysfunction: a systematic review and meta-analysis. Int Urol Nephrol 2017;49(10):1731–40. DOI: 10.1007/s11255-017-1644-5. PMID: 28741090.
10. Evans JD, Hill SR A comparison of the available phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction: a focus on avanafil. Patient Prefer Adherence 2015;9:1159–64. DOI: 10.2147/ PPA.S56002. PMID: 26316720.
11. Bolat MS, Cinar O., Akdeniz E., Aşcı R. Low dose daily versus on-demand high dose tadalafil in diabetic patients with erectile and ejaculatory dysfunction. Int J Impot Res 2018;30(3):102–7. DOI: 10.1038/s41443-018-0019-5. PMID: 29795527.
12. Aversa A., Fittipaldi S., Francomano D. et al. Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization. Endocrine 2017;56(3):639–48. DOI: 10.1007/ s12020-016-1208-y. PMID: 28133708.
13. Maneschi E., Cellai I., Aversa A. et al. Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: studies in rabbits. Mol Cell Endocrinol 2016;424:50–70. DOI: 10.1016/j.mce.2016.01.015. PMID: 26805634.
14. Ozcan L., Polat EC, Kocaaslan R. et al. Effects of taking tadalafil 5 mg once daily on erectile function and total testosterone levels in patients with metabolic syndrome. Andrologia 2017;49(9). DOI: 10.1111/and.12751. PMID: 28295481.
15. Maresca L., D'Agostino M., Castaldo L. et al. Exercise training improves erectile dysfunction (ED) in patients with metabolic syndrome on phosphodiesterase-5 (PDE-5) inhibitors. Monaldi Arch Chest Dis 2013;80(4):177–83. DOI: 10.4081/monaldi.2013.5234. PMID: 25087294.
16. Grimsley SJ, Khan MH, Jones GE Mechanism of phosphodiesterase 5 inhibitor relief of prostatitis symptoms. Med Hypotheses 2007;69(1):25–6. DOI: 10.1016/j.mehy.2006.11.040. PMID: 17300876.
17. Kurita M., Yamaguchi H., Okamoto K. et al. Chronic pelvic pain and prostate inflammation in rat experimental autoimmune prostatitis: effect of a single treatment with phosphodiesterase 5 inhibitors on chronic pelvic pain. Prostate 2018;78(15):1157–65. DOI: 10.1002/pros.23690. PMID: 30009466.
18. Nishino Y., Miwa K., Moriyama Y. et al. Tadalafil ameliorates symptoms of patients with benign prostatic hyperplasia complicated by chronic pelvic pain syndrome. Hinyokika Kiyo 2017;63(3):101–5. DOI: 10.14989/ActaUrolJap_63_3_101. PMID: 28331166.
19. Kirby RS, Carson C. 3rd, Dasgupta P. Daily phosphodiesterase type 5 inhibitor therapy: a new treatment option for prostatitis/prostatodynia? BJU Int 2014;113(5):694–5. PMID: 24877211.
20. Glybochko P.V., Alyaev Yu.G., Esilevsky Yu.M. et al. Selection of phosphodiesterase type 5 inhibitors for the treatment of patients with erectile dysfunction and chronic prostatitis. Sechenovskiy Vestnik 2013;2(12):33–40.
21. Blumberg B.I., Shatylko T.V., Tverdokhleb S.A. and others. Combination therapy of prostatitis-associated copulative dysfunction. Urology 2014;(6):27–32. .
22. Kamalov A.A., Takhirzade A.M. Modern approaches to conservative treatment of men with a combination of benign prostatic hyperplasia and erectile dysfunction. Urology 2017;(6):160–3. . DOI: 10.18565/urology.2017.5.160-163. PMID: 30035422.
23. Jannini EA, Isidori AM, Gravina GL et al. The ENDOTRIAL study: a spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction. J Sex Med 2009;6(9):2547–60. DOI: 10.1111/j.1743-6109.2009.01375.x. PMID: 19570039.
24. Özkıdık M., Gökce M.I., Yaman O. Efficacy of tadalafil treatment on erectile dysfunction in patients under dutasteride treatment: a prospective non-randomized comparative study. Turk J Urol 2018;44(4):294–7. DOI: 10.5152/tud.2018.46666. PMID: 29799405.
25. Kim SW, Park NC, Lee SW et al. Efficacy and safety of a fixed-dose combination therapy of tamsulosin and tadalafil for patients with lower urinary tract symptoms and erectile dysfunction: results of a randomized, double-blinded, activecontrolled trial. J Sex Med 2017;14(8):1018–27. DOI: 10.1016/j. jsxm.2017.06.006. PMID: 28760246.
26. Karami H., Hassanzadeh-Hadad A., Fallah-Karkan M. Comparing monotherapy with tadalafil or tamsulosin and their combination therapy in men with benign prostatic hyperplasia: a randomized clinical trial. Urol J 2016;13(6):2920–6. PMID: 27928815.
27. Yoshida T., Kinoshita H., Shimada S. et al. Comparison of silodosin monotherapy vs silodosin with tadalafil add-on therapy in patients with benign prostatic hyperplasia. Urology 2017;106:153–9. DOI: 10.1016/j.urology.2017.04.012. PMID: 28431996.
28. García-Perdomo HA, Echeverría-García F., Tobías A. Effectiveness of phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction in patients with spinal cord trauma: systematic review and metaanalysis. Urol Int 2017;98(2):198–204. DOI: 10.1159/000448290. PMID: 27509143.
29. Burdin K.A., Kyzlasov P.S., Martov A.G. and others. Erectile dysfunction in multiple sclerosis. Medicine in Kuzbass 2017;16(3):17–22. .
30. Lombardi G., Macchiarella A., Del Popolo G. Efficacy and safety of tadalafil for erectile dysfunction in patients with multiple sclerosis. J Sex Med 2010; 7(6):2192–200. DOI: 10.1111/j.1743-6109.2010.01797.x. PMID: 20384939.
31. Francomano D., Ilacqua A., Cortese A. et al. Effects of daily tadalafil on lower urinary tract symptoms in young men with multiple sclerosis and erectile dysfunction: a pilot study. J Endocrinol Invest 2017;40(3):275–9. DOI: 10.1007/s40618-016-0557-y. PMID: 27752863.
32. Lombardi G., Nelli F., Celso M. et al. Treating erectile dysfunction and central neurological diseases with oral phosphodiesterase type 5 inhibitors. Review of the literature. J Sex Med 2012;9(4):970–85. DOI: 10.1111/j.1743-6109.2011.02615.x. PMID: 22304626.
33. Drobnis EZ, Nangia AK Phosphodiesterase inhibitors (PDE inhibitors) and male reproduction. Adv Exp Med Biol 2017;1034:29–38. DOI: 10.1007/978-3-319-69535-8_5. PMID: 29256125.
34. Yang Y., Ma Y., Yang H. et al. Effect of acute tadalafil on sperm motility and acrosome reaction: in vitro and in vivo studies. Andrologia 2014;46(4):417–22. DOI: 10.1111/and.12097. PMID: 23581543.
35. Corvasce A., Albino G., Leonetti T. et al. Once-a-day tadalafil administration improves the spermogram parameters in fertile patients. Arch Ital Urol Androl 2015;87(3):210–3. DOI: 10.4081/aiua.2015.3.210. PMID: 26428642.
36. Paduch DA, Bolyakov A., Polzer PK, Watts SD Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies. BJU Int 2013;111(2):334–43. DOI: 10.1111/j.1464-410X.2012.11656.x. PMID: 23356749.
37. Sontag A., Ni X., Althof SE, Rosen RC Relationship between erectile function and sexual self-confidence: a path analytic model in men being treated with tadalafil. Int J Impot Res 2014;26(1):7–12. DOI: 10.1038/ijir.2013.31. PMID: 23864107.

The article was published in the journal “Andrology and Genital Surgery” issue No. 4 2021, pp. 15-20

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Andrology and genital surgery 2021 No. 4

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Features of pharmacokinetics and effectiveness of tadalafil with daily use (literature review)

Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient for sexual intercourse [1]. Despite the non-life-threatening nature of the disease, ED is interconnected with the physical and psychosocial health of men and has a significant impact on the quality of life of both the patients themselves and their partners/families [2–4]. Currently, the first-line therapy for the treatment of ED is selective phosphodiesterase type 5 inhibitors (PDE5 inhibitors) [5], most often tadalafil, sildenafil and vardenafil [6]. All of these drugs are highly effective in the treatment of ED of various etiologies, although their pharmacokinetics and safety profile differ [7]. For example, unlike other PDE5 inhibitors, consumption of fatty foods and alcohol do not affect the absorption of tadalafil [8]. Its maximum concentration in blood plasma is achieved 2 hours after administration (and not after 1 hour, as is the case with sildenafil and vardenafil). A distinctive feature of tadalafil is also its long half-life - 17.5 hours (along with high, significant activity expected from clinical studies within 24 hours after taking the drug) [9]. In addition, tadalafil at a dosage of 5 mg/day. registered for use in the Russian Federation at the very beginning of 2011 and is the only PDE-5 inhibitor with the possibility of daily administration. The possible potential benefits of taking PDE5 inhibitors daily have been discussed and studied for a long time. One of the theoretical advantages is the absence of a relationship between the drug and sexual activity (the so-called sexual spontaneity), along with the minimization of side effects from taking the drug in patients with poor tolerance to high doses of PDE5 inhibitors [10,11]. The extended half-life provides tadalafil with an “ideal situation” to achieve a constant required blood concentration when taken daily. The multicenter randomized study comparing two options for taking tadalafil (SURE) is one of the first studies to study the characteristics of chronic use of the drug. This 12-week crossover study included 4262 patients with ED. All patients were randomized to receive 20 mg tadalafil 3 times/week. and a group receiving a similar dosage “on demand”. Normalization of erectile function in general was noted by more than 60% of patients. More than 70% of patients in both groups were able to achieve the erection necessary to begin and complete sexual intercourse (before the start of the study, this figure was 21%). The authors noted no significant difference in effectiveness between the two options for taking the drug [12–14]. The results of this, as well as many other studies, have led to a paradigm shift in the treatment of ED. Currently, this disease has moved from the category of situational (i.e., requiring treatment “on demand”) to the category of chronic diseases with the option of permanent conservative therapy. This article analyzes studies completed by 2011 on the pharmacokinetics, as well as the effectiveness and safety of daily routine use of low doses of tadalafil for the treatment of ED. The search was performed using the PubMed database. Particular attention was paid to randomized trials. Overview of the pharmacokinetic characteristics of tadalafil It is known that tadalafil is approximately 700 times more selective for PDE5 than for PDE6, found in the retina [8]. Moreover, tadalafil has a lower affinity for PDE6 compared to sildenafil or vardenafil [15]. This fact may explain the lower number of ophthalmological complications encountered when taking tadalafil compared to analogues [16]. On the other hand, the presence of a significantly greater number of side effects in the form of myalgia and lower back pain when taking tadalafil is explained by the relatively high affinity of the drug for PDE-11, present in skeletal muscles [17]. It is known that tadalafil has a prolonged half-life, which is ensured by a low level of distribution, delayed hepatic clearance and the presence of an 80% bioavailability level [8,18]. The drug reaches its maximum concentration in the blood 2 hours after use, the effect is noted after 15 minutes. after administration, the effect lasts for 36 hours [19]. Tadalafil is metabolized into a catechol metabolite with subsequent excretion mainly in feces. At a dosage of 2.5–20 mg, tadalafil has linear pharmacokinetic characteristics [18]. When taken daily, the drug reaches a stable concentration in plasma after 5 days of use, and the concentration is 1.6 times higher than with a single dose [18]. In other words, the cumulative content of tadalafil in plasma with a daily dose of 5 mg corresponds to a similar indicator with a situational dose of 8 mg of the drug [20]. A study modeling the pharmacokinetics of tadalafil when administered daily suggested that a 5 mg dose would result in a plasma concentration of 55 ng/mL. This value is sufficient to inhibit 90% of PDE5 in vitro. The presence of the specified concentration level is associated with the clinical effectiveness of the drug and is sufficient to provide an erectogenic effect. When a steady-state concentration is reached, daily intake of 5 mg of tadalafil leads to a maximum peak concentration lower than when using 10–20 mg of the drug 2–3 times/week. [21]. From these data it follows that a patient who notes the presence of side effects due to increased concentrations of the drug in plasma is advised to take tadalafil daily, since the maximum peak concentration of the drug in this case will be lower. In this case, the efficiency decreases slightly. One study compared two regimens of tadalafil: 2.5–5 mg daily and 10–20 mg ad hoc. Interestingly, the incidence of headaches was 2–3 times lower in patients taking the drug daily [22]. It is known that ketoconazole, protease inhibitors, and grapefruit juice can slow down the excretion of tadalafil, so patients taking these substances are advised to take the drug situationally or take a minimum daily dose of 2.5 mg [8]. Data from pharmacokinetic studies indicate a slower excretion of tadalafil in patients with impaired liver function, which dictates the need to prescribe the minimum possible dose of the drug to this group of patients. Considering the contraindications for combined use with nitrates, tadalafil should be prescribed with caution to patients with a history of cardiovascular pathology. It is known that the synergistic effect of combined use of PDE5 inhibitors with nitrates can lead to life-threatening hypotension [23]. Review of the effectiveness of daily tadalafil In 2004, McMahon et al. published the results of one of the first studies that examined the use of tadalafil for the treatment of ED. The study included 112 men with ED of various etiologies who had unsuccessfully taken tadalafil 20 mg at least 6 times. These patients were then offered situational treatment with tadalafil at a dosage of 20 mg for 4 weeks. followed by a 4-week washout period and 12 weeks. taking 10 or 20 mg tadalafil daily. 101 patients completed the study. There was a significant improvement in the mean IIEF score (ED domain) from 10.3 to 14.9 points after 4 weeks. situational intake and up to 23.1 points after 12 weeks. taking the drug daily. The most important point was the normalization of IIEF ED values ​​(more than 26) in 41 and 32% of patients after daily therapy compared to the no therapy group after the situational treatment phase [24]. The same authors in 2005 conducted a randomized, open crossover comparative study of 12-week therapy with tadalafil in doses of 10 mg daily and 20 mg situationally. The study involved 145 patients with ED, suffering from this disease for more than 6 months. 122 patients completed the study. The initial IIEF ED score was 14.6 points. This indicator increased significantly – to 23.2 and 26.4 points in the groups of situational and daily drug use, respectively. Normalization of IIEF ED values ​​(more than 26) was observed in 57 and 73% of patients in the situational and daily intake groups, respectively. Interestingly, 72% of patients preferred to take the drug daily after the end of the study [25]. Porst et al. in 2006, studied the effectiveness and safety of daily administration of 5 and 10 mg tadalafil in a multicenter, parallel, randomized, placebo-controlled study. 293 patients with ED took part in this work. The duration of therapy was 12–15 weeks. 87.3% of participants completed the study. Both dosages significantly improved erectile function as assessed by IIEF ED domain scores, with increases of 9.7, 9.4, and 0.9 points noted for the 5 mg, 10 mg, and placebo groups, respectively. In this work, the effectiveness of therapy was also assessed using the SEP questionnaire, consisting of 5 questions: • SEP1 – was the penis erect during sexual activity? • SEP2 – were you able to insert the penis into your partner's vagina? • SEP3 – was your erection long enough to successfully complete sexual intercourse? • SEP4 – are you satisfied with the degree of your erection? • SEP5 – are you generally satisfied with your sexual activity? Although this questionnaire is subjective in nature, it helps assess the effectiveness of any drug taken using “yes” and “no” answers [26]. The SEP2 positive rate was 79.4, 81.2 and 51.7% in the 5 mg, 10 mg and placebo groups, respectively [20]. In 2007, Rajfer et al. conducted a multicenter, randomized, placebo-controlled study of tadalafil at doses of 2.5 and 5 mg daily in men with ED. The study included 238 patients. The results of the work revealed greater effectiveness when taking both dosages of the drug compared to placebo. Tadalafil also had a positive effect on indicators such as satisfaction with sexual intercourse and overall satisfaction with sexual life [27]. In 2008, Hatzichristou et al. investigated the effectiveness of daily administration of tadalafil (2.5 mg) in patients with diabetes mellitus and ED in a multicenter 24-week randomized trial. Of the 298 patients included in the study, 254 completed the protocol (85%). Tadalafil was found to be significantly superior to placebo at both dosages across all measures. The IIEF ED domain increased by 4.8 and 4.5 points in the 2.5 and 5 mg tadalafil groups, respectively, compared with 1.3 points in the placebo group. The mean change in positive response for SEP2 was 20, 29 and 5% in the 2.5 mg, 5 mg and placebo groups, respectively, and for SEP3 - 26, 25 and 8% in the 2.5 mg, 5 mg and placebo groups, respectively. There were no changes in biochemical blood parameters indicating inflammatory activity [28]. A number of studies have been conducted to examine the effects of daily use of tadalafil on satisfaction with the sexual activity of patients' partners. One study compared situational administration of sildenafil and tadalafil. As a result, it turned out that 79% of women prefer taking tadalafil, which can be explained by the longer action of the drug and, accordingly, greater flexibility in planning sexual activity [29]. In 2009, Rubio-Auriolis et al. studied partner satisfaction in a multicenter randomized trial of daily tadalafil 5 mg versus placebo for 12 weeks. in men with ED. The study included 342 couples, and 307 couples (90%) completed the study. Before the study, partners were interviewed using the FSFI questionnaire, with a score of less than 26.55 points the couple was excluded from the analysis. Baseline IIEF ED values ​​were 15.8 and 15.1% in the tadalafil and placebo groups, respectively. At the end of the study, the IIEF ED score increased by 7.9 and 0.7 points in the tadalafil and placebo groups, respectively; changed to positive responses on SEP2 - by 29 and 3% and on SEP3 - by 46 and 11%, respectively. Couples in the treatment group reported a significantly greater improvement in the quality of sexual life compared to the placebo group, which was reflected in an increase in the frequency and duration of sexual intercourse, satisfaction with sexual intercourse and sexual activity in general. In 2010, Althof et al. summarized the results of the Rubio-Auriolis [30] and Porst [20] studies with the aim of verifying the high effectiveness of treatment for ED and improving the quality of sexual life in 473 couples. The authors found a significant relationship between the ability to achieve an erection and sexual satisfaction [31]. From all of the above, it becomes clear that many studies conducted on the characteristics of daily use of tadalafil reliably prove the high effectiveness of using the drug for the treatment of ED of various etiologies. It also becomes clear that daily use of tadalafil has a pronounced positive effect on sexual relationships between partners. Review of the safety of daily tadalafil Adverse events (AEs) in studies of daily tadalafil were mostly mild [20,22]. In most studies, no serious AEs were noted. In studies with registered serious AEs, the researchers did not note any association with the drug [20,30]. Although the majority of AEs were mild, it should be noted that the long half-life of tadalafil could theoretically contribute to a longer duration of AEs compared to other PDE5 inhibitors (with a short half-life) [32]. In an open study of the characteristics of taking tadalafil, 53% of patients noted at least one AE during the year, 73% within 2 years of therapy [33]. Typically, the incidence of AEs decreased as therapy continued [33]. When taking the drug situationally, the frequency of “troubling” AEs (headache, back pain, dyspepsia) did not exceed 10% [22]. Dropout from the study due to AEs was observed in 1–6% of cases [20,24,25,33], while a higher dropout rate of about 10% was observed with ad hoc administration of 20 mg tadalafil. The most common AEs were headache (1–14%), dyspepsia (1–11%), facial flushing (7–8%), nasal congestion (6–7%), back pain (2–11%), myalgia (1–5%), abdominal pain (3–9%), nausea (1–4%) [20,24,25,33]. In some studies, AEs were reported more frequently with higher doses of tadalafil [24,34], but a dose-dependent relationship was not confirmed in every study [20,35]. In at least one study, the incidence of AEs did not differ between treatment and placebo groups [30]. Cardiovascular safety profile Tadalafil has a favorable cardiovascular safety profile, without significantly worsening the course of coronary artery disease and unstable hemodynamics; does not cause changes in the ECG, deterioration of clinical and laboratory parameters and does not increase the incidence of cardiovascular diseases in patients taking the drug compared to placebo [8,21,33]. Tadalafil did not cause QT prolongation; there have been no reports of increased mortality in patients taking the drug [36]. However, it must be remembered that the simultaneous use of tadalafil and nitrates is strictly contraindicated [23]. Various studies examining the combined use of tadalafil with a-blockers have demonstrated a low incidence of clinically significant hypotension (this applied to all tadalafil dosing regimens) [37]. Ophthalmic Safety Profile A study was conducted that examined the profile of ophthalmic AEs in 244 patients randomized to tadalafil, sildenafil 50 mg, or placebo. There was a significantly more pronounced increase in beta wave amplitude during electroretinography in response to a light stimulus in the tadalafil group compared to placebo. There were no other statistically significant differences between the groups. The authors concluded that there were no clinically significant ophthalmic side effects with daily use of the drug [15]. Effect of tadalafil on ejaculate characteristics Hellstrom et al. studied the effect of high-dose daily therapy with tadalafil 20 mg for 9 months. with a 6-month observation period on reproductive parameters of men over 45 years of age. The authors found a 50% decrease in sperm concentration in 2 (2%) patients in the placebo group and in 12 (13%) patients in the tadalafil group. Despite the fact that after 6 months. Observations after completion of therapy, the concentration of sperm returned to the original in 8 of 12 patients in the Tadalafil group and in one of 2 patients in the placebo group, the authors concluded that the high -quality composition of the ejaculate when taking high doses of tadalafil [34]. The conclusion in our opinion, the results of clinical studies are sufficient to conclude about the effectiveness of the daily intake of Tadalafil. Tadalafil is the first IFDE -5 used daily for the treatment of Ed. This drug, which has great efficiency and high safety profile, can be proposed for use by almost any patient suffering from ED. There is no doubt that studies on the study of the effect of a long and constant administration of the drug (regarding the improvement of the actual erection and the functions of the endothelium of cavernous bodies) will continue. Currently, groups of patients are formed for whom a daily intake of Tadalafil 5 mg is the optimal method for the treatment of ED. Literature 1. NIH Consensus Conference // Jama. 1993 jul. Vol. 7. 270 (1). R. 83. 2. Impotence and Its Medical and Psychosocial Correlates: Results of the Massachusetts Male Aing Study Feldman Ha et al. // J. Urol. 1994 Jan. Vol. 151 (1). P. 54. Abstract. 3. Feldman Ha et al. Erectile Dysfunction and Coronary Risk Factors: Prospective Results from the Massachusetts Male Anging Study // Prev Med. 2000. Vol. 30(4). R. 328–338. Abstract. 4. Fisher Wa, Eardley I., McCabe M., Sand M. Erectile Dysfunction (Ed) IS A Shard Sexual Concern of CounS II: Association of Female Partner Chartner ED Reatment Seeking and Phosphorus Type 5 Inhibitor Utilization // J Sex med. 2009. Vol. 6 (11). R. 3111–3124. Abstract. 5. Tsertsvadze A., Fink Ha, Yazdi F., Macdonald R., Bella aj et al. Oral Phosphorus -5 Inhibitors and Hormonal Treatments for Erectile Dysfunction: A Systematic Review and Meta - Angels // Ann Internet med. 2009. Vol. 151 (9). R. 650–661. Abstract. 6. Shindel AW 2009 Update on Phosphorus Type 5 Inhibitor Therapy Part 2: Updates on Optimal Utilization for Sexual Concerns and Rare Toxicits in this class // J Six Med. 2009. Vol. 6 (9). R. 2352–2364. Quiz 2365–2366. Abstract. 7. PDE5 inhibitors: are the there differences? // Can J Urol. 2006. Vol. 13 (SUPPL 1). R. 34–39. Abstract. 8. COWARD RM, Carson CC Tadalafil in the Treatment of Erectile Dysfunction // Ther Clin Risk Manag. 2008. Vol. 4. R. 1315–1330. Abstract. 9. Eardley I., Cartledge J. Tadalafil (Cialis) For Men with Erectile Dysfunction // Int j Clin Pract. 2002. Vol. 56. R. 300–304. Abstract. 10. Hanson - Divers C., Jackson SE, LE TF, CRAWFORD SY, ROSEN RC Health Outcomes Variaans Important to the Treattion of Eresfunction // J Urol. 1998. Vol. 159 (5). R. 1541–1547. Abstract. 11. Costa P., Grivel T., Geechchan N. Tadalafil Onte Daily in the Management of Erectile Dysfunction: Patient and Partner Perspectives // Patient Prefer Adchereence. 2009. Vol. 3. R. 105–111. PDE -5 Inhibitor Therapy and Edstion. 12. MIRONE V. et al. An evaluation of an alternate Dosing Regimen with Tadalafil, 3 Times/Week, For Men with Erectile Dysfunction: Sure Study in 14 European countries // EUR UROL. 2005. Vol. 47. R. 846–854. Discussion 854. 13. Costa P. et al. Predictors of Tadalafil Efficacy in Men Erectile Dysfunction: The Sure Study Comparing Two Dining Regimens // J Sex Med. 2006. Vol. 3. R. 1050–1058. Results. 14. Moncada I. et al. 2005. Vol. 2. R. 668–674. Results. 15. Cordell with et al. Retinal Effects of 6 Months of Daily Use of Tadalafil or Sildenafil // Arch Ophthalmol. 2009. Vol. 127. R. 367–373. Results. 16. Bischoff E. Potency, Selectivity and Consequences of Nonselectivity of PDE Inhibition // Int J Impot Res. 2004. Vol. 16 (SUPPL 1). R. 11–14. Abstract. 2009. Vol. 103 (10). R. 1392–1395. Abstract. 18. Forgue st et al. Tadalafil Pharmacokinetics in Healthy Subjects // Br J Clin Pharmacol. 2006. Vol. 61. R. 280–288. P 282 Results 19. Rosen Rc et al. Determining the Earliest Time Within 30 Minutes to Erectogenic Effect after Tadalafil 10 and 20 Mg: A Multicenter, Randomized, Double - Blind, Placebo - Controlled, At - Home Study X med. 2004. Vol. 1. R. 193–200. Abstract. 20. Porst H. et al. Evaluation of the Efficacy and Safety of - a - a - day do -a -date of Tadalafil 5 mg and 10 mg in the Treatment of Eretment Dysfunction: Results of a MultiCenter, Randomized, D feic D, Placebo - Controlled Trial // EUR UROL. 2006. Vol. 50. 351–359. Results. 21. Wrishko R., Sorsaburu S., Wong D., Strawbridge A., McGill J. Safety, Efficacy, and Pharmacokinetic Over -Dose Daily Administration of Tadalapalfil // J Sex Med. 2009. Vol. 6. R. 2039–2048. Pharma Part. 22. Donatucci CF et al. Efficacy and Safety of Tadalafil Once Daily: Considerations for the Practical Application of a Daily Dosing Option // Curr Med Res Opin. 2008. Vol. 24. R. 3383–3392. Discussion. 23. Kloner Ra et al. Time Course of the Intection Between Tadalafil and Nitrates // J Am Coll Cardiol. 2003. Vol. 42. R. 1855–1860. Abstract. 24. McMahon C. Efficacy and Safety of Daily Tadalafil in Men with Erection Dysfunction PreviousSly unresponsive to - decodalafil // J Sex med. 2004. Vol. 1. R. 292–300. Abstract. 25. McMahon C. Comparison of Efficacy, Safety, and Toleability of OF ON - DEMAND TADALAFILA and Daily DOSED TADALAFIL FOR THE TREATMENT OF ERECTILE DYSFUNCTION // J SEX MED. 2005. Vol. 2. p. 415–425. Discussion. 26. Shabsigh R. et al. RELIABILITY OF EFFICY in Men with Erection Dysfunction Treated with Tadalafil Onile Inter Initial Success // Inter J Impot Res. 2010. Vol. 22 (1). R. 1–8. Abstract. 27. Rajfer J. et al. Tadalafil Dated ONCE A Day with with Erectile Dysfunction: A RANDOMIZED, DOBLE - BLIND, PLACEBO - CONTROLLLED StUDY in the US // Int J Impot Res. 2007. Vol. 19. p. 95-103. Abstract. 28. Hatzichristou D. et al. Efficacy of Tadalafil Once Daily in with Diabetes Mellitus and Erectile Dysfunction // Diabet Med. 2008. Vol. 25. R. 138–146. Abstract. 29. Conaglen HM, Conaglen JV Investigating Women's Preference for Sildenafil or Tadalafil Use by Their Partners with Erements Dysfunction: The Partners' Preference Magic Ed. 2008. Vol. 5. R. 1198–1207. Abstract. 30. Rubio - aurioles E. et al. Impact ON ERECTILE FUNCTION AND Sexual Quality of Life of Coupeles: A Double - Blind, Randomized, Placebo - Controlled Trial of Tadalafil Taken Once Daily // J Sex Med. 2009. Vol. 6. R. 1314–1323. Abstract. 31. Althof Se et al. Impact of Tadalafil Onile in Men with Erection Dysfunction - Including a Report of the Partners' evaluation // Urology. 2010. Vol. 75 (6). R. 1358–1363. Abstract. 32. Taylor J., Baldo Ob, Storey A., Cartledge J., Eardley I. Differences in Side - Effect Duration and Related Bother Levels Between Phosphorase Type 5 Inhibitors // BJUU . 2009. Vol. 103 (10). R. 1392–1395. Abstract. 33. Porst H. et al. Long - Term Safety and Efficacy of Tadalafil 5 Mg Dined Onte Daily in Men with Erete Dysfunction // J Sex Med. 2008. Vol. 5. R. 2160–2169. Abstract. 34. Hellstrom wj et al. An evaluation of Semen Characteristics in Men 45 Years of Age Or Older Daily Daily Daily Tadalafil 20 Mg: Results of a MultiCenter, Randomized - BLIND, PLACEBO - Controlled 9 - Month Study // EUR UROL. 2008. Vol. 53. R. 1058–1065. Abstract. 35. Porst H. et al. Effects of Once - Daily Tadalafil on Erection in Men with Erection Dysfunction and Signs and Symptoms of Benign Prostatic Hyperplasia // EUR UROL. 2009. Vol. 56. R. 727–735. 36. Beasley CMJR. et al. The Combined Use of Ibutilide as an Active Control with Intensive Electrocardiographic Sampling and Signaging AS A Sensitive Method to Assess of the Effects of TadalArfilon He Human Qt Interval // J Am Coll Cardiol. 2005. Vol. 46. ​​R. 678–687. Abstract. 37. Kloner Ra et al. Cardiovascular Safety Update of Tadalafil: Retrospective Analysis of Data From Placebo - Clinical Clinical Trials of Tadalafil with AS NEEDED OR ONCE - A - DAY DOSING // Am J Cardiol. 2006. Vol. 97. R. 1778–1784. Abstract.