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The Daily Therapy With L-Arginine 2,500 mg and Tadalafil 5 mg in Combination and in Monotherapy for the Treatment of Erectile Dysfunction: A Prospective, Randomized Multicentre Study

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract

Introduction

A synergistic effect of the combination therapy tadalafil plus L-Arginine is conceivable in patients affected by erectile dysfunction (ED).

To evaluate the effectiveness and tolerability of tadalafil 5 mg and L-Arginine 2.5 grams in monotherapy and combination therapy.

Methods

Recruited patients completed the International Index of Erectile Function – Erectile Function domain (IIEF-EF) and Sexual Encounter Profile diaries completed at baseline and after treatment. The survey was randomized into 3 groups with an equal allocation ratio. Group A received daily L-Arginine 2,500 mg, group B received daily tadalafil 5 mg, and group C received both daily L-Arginine 2,500 mg plus daily tadalafil 5 mg. The duration of therapy in all 3 groups was 12 weeks. Safety was assessed by evaluating all reported treatment-emergent adverse events.

Main Outcome Measure

The main outcome measure was the change in IIEF-EF score and in per-patient percentage of “yes” responses to Sexual Encounter Profile Question 3 from baseline to after treatment.

Results

300 eligible patients were enrolled, and 100 subjects for each group were allocated. Based on the IIEF-EF score, the participants were divided into 3 categories: severe, moderate, and mild ED. IIEF-EF score increased in group A from 15 ± 7 to 18.1 ± 9.2, in group B from 14.8 ± 6.9 to 20.8 ± 7.3, and in group C from 14.9 ± 7.1 to 22 ± 7.5. In mild ED group, the mean IIEF-EF score increased from 22.1 ± 2.2 to 27.5 ± 2.3 in group A; from 22.1 ± 2.2 to 27.8 ± 2 in group B, and from 22.2 ± 2.2 to 29.3 ± 0.9 in group C. We report a total of 11, 53, and 67 cases of adverse events in group A, B, and C respectively.

Conclusions

Combination therapy was superior to monotherapies.

Gallo L, Pecoraro S, Sarnacchiaro P, et al. The Daily Therapy With L-Arginine 2,500 mg and Tadalafil 5 mg in Combination and in Monotherapy for the Treatment of Erectile Dysfunction: A Prospective, Randomized Multicentre Study. Sex Med 2020;8:178–185.

Introduction

Erectile dysfunction (ED) is a very common disease affecting millions of individuals worldwide, which is defined as the inability to achieve or maintain an erection sufficient for a satisfactory sexual activity.1 The prevalence of this condition increases with age affecting the 52% of men aged between 40 and 70 years.2 Phosphodiesterase type 5 inhibitors (PDE5is) are currently the first-line treatment for any type and etiology of ED.3 In particular, the PDE5i with a longer duration of action as that of tadalafil has a half-life of >17 hours, and provides greater flexibility, less anxiety, and major spontaneity to sexual activity.4 Tadalafil provides a continuous PDE5 inhibition levels sufficient for ED treatment in most patients.5 However, PDE5is are not always the adapted treatment because a selected subgroups of patients, the so called “difficult to treat” populations affected by severe ED, remains refractory to these molecules.6 Penile erection is determined by a dynamic vascular process involving relaxation of the arterial and trabecular smooth muscle in the corpora cavernosa.7 The essential mediator required for penile erection is nitric oxide (NO).8 NO binds to guanylate cyclase inside the cells of vascular smooth muscle generating the cyclic guanosine monophosphate that acts as a second messenger to exert relaxation and vasodilation determining the penile erection.9 NO is generated by an enzyme named NO synthase, whose only physiological substrate is the semiessential amino acid L-arginine.10 Because an increased concentration of the substrate leads to a higher amount of NO into account, L-arginine was showed in many studies being an effective treatment for ED, especially for patients affected by mild to moderate ED.11 In particular, the natural origin of this amino acid, its good bioavailability after oral absorption, and its excellent tolerance allowing long-course therapy has made arginine a widely used supplement by men seeking natural treatment and/or self-medication for ED.12 Since PDE5i enhance NO activity and require this molecule to exert their action, is conceivable a synergistic therapeutic approach based on the concomitant subscription of these molecules with L-Arginine. However, surprisingly, although both tadalafil and arginine were already evaluated in combination therapy with many others drugs or supplements in several studies, to the best of our knowledge, the synergistic and concomitant subscription of these 2 molecules was never been investigated. The aim of this prospective, randomized, multicenter study was to evaluate the effectiveness and tolerability of tadalafil 5 mg and L-Arginine 2.5 gm in monotherapy and combination therapy in patients affected by various grades of ED.

Methods

All patients affected by ED who came to our 4 centers specialized in male sexual dysfunction were considered for recruitment in this prospective, randomized, multicenter, three-arm study. The diagnosis of ED at first consultation was based on sexual and medical history, physical examination, and standard laboratory analysis. For all recruited patients, age, marital status, cigarette smoking, full medical history, and current therapy were recorded. At the baseline visit, all patients completed the Italian translation of the 2 questionnaires: the International Index of Erectile Function-erectile function (IIEF-EF) domain (defined as the sum of responses to IIEF questions 1–5 and 15) and Sexual Encounter Profile (SEP) diaries. Both the 2 questionnaires (IIEF-EF and SEP diaries) have been shown to be simple, reliable, and valid tools for the assessment of erectile function in clinical trials research.13 , 14 The inclusion criteria of the present study were: age ≥18 years, patients suffering from ED for at least 3 months, an IIEF-EF score totalized at first consultation ≤25 (IIEF-EF score can range from 1, severe ED, to 30, normal erection), and men in a stable relationship desiring an active heterosexual life. The exclusion criteria were: kidney disease of any type and severity, macroalbuminuria, severe retinopathy, liver failure, coronary heart disease, peripheral or cerebrovascular disease, diabetic or non-diabetic neuropathy, endocrine diseases, pelvic surgery, drug or alcohol abuse, testes hypotrophy, Peyronie’s disease, and major psychiatric disorders. The following medications were contraindicated during the trial: nitrates, estrogens, antiandrogens, anxiolytic drugs, LH-RH analogs, and tricyclic antidepressants. The consumption of other drugs that may have affected erectile disorders and may have been prescribed once a patient had entered the trial was restricted. Patients who had previously received one of the trial treatments within 30 days before inclusion into the trial were also excluded. Patients were recruited based on the total score of the IIEF-EF questionnaire and were further divided into 3 categories: severe ED (score 1–10), moderate ED (score 11–17), and mild ED (score 18–25). All patients were asked to sign an informed consent form in conformity with the Declaration of Helsinki. The ethics committees of all participating institutions approved the study. All eligible patients were randomized in 3 groups with an equal allocation ratio (1:1:1). The randomization sequence was generated using a computer by the study coordinating team. Treatment allocation was communicated by the coordinating center to the investigators through a web-based registration system to ensure allocation concealment and minimize bias. Recruited patients were treated as follows: group A received L-arginine 2,500 mg daily, group B received tadalafil 5 mg daily, and group C received both L-arginine 2,500 mg plus tadalafil 5 mg daily. The duration of the therapy in all 3 groups was 12 weeks. At the end of treatment, all the subjects underwent a second visit where they again completed the IIEF-EF questionnaire and the SEP diaries Figure 1 ). All patients were examined in each center by a certified urologist specialized in male sexual dysfunction who evaluated the adverse events (AEs) and assisted patients to fill the questionnaires at the baseline and at the control visit.

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The main outcome measures were the changes from the baseline to after treatment in the IIEF-EF score and in the per-patient percentage of “yes” responses to SEP question 3 (SEP3: “Did your erection last long enough for you to have a successful intercourse?”).

Safety was assessed by evaluating all reported treatment-emergent AEs and standard safety laboratory assessments for all randomized patients. Treatment-emergent AEs were defined as any AE that first occurred or worsened after randomization and were mapped with the Medical Dictionary for Regulatory Activities.

At the beginning of the study, the one-way analysis of variance (ANOVA) was performed at the baseline to verify the homogeneity of the 3 groups related to all the parameters evaluated. Subsequently, to check the efficacy of all the 3 therapeutic protocols evaluated in the present study, the mean IIEF-EF scores before and after treatment were compared by Student’s t-test, whereas the per-patient percentage of “yes” responses to SEP 3 before and after treatment was analyzed by a z test (hypothesis tested for means and proportions, respectively.) In the first case, the hypothesis of homogeneity of variances was preliminarily verified. This verification concerned both the overall sample and the 3 ED severity class subgroups (mild, moderate, and severe).

To test the superiority of a protocol with respect to the others (A vs B, A vs C, and B vs C), once the homogeneity of the 3 groups was verified at the baseline, we compared the improvements in the IIEF-EF score obtained by the 3 treatments considering both the overall population and the 3 ED severity categories. This analysis was executed using the one-way ANOVA considering the differences as variables in the mean IIEF-EF score before and after the treatment. If the null hypothesis was rejected, each pair of the mean IIEF-EF score was compared through 3 different statistical tests: LSD, Bonferroni, and Scheffè. For each pair of IIEF-EF scores (before and after treatment), the null hypothesis was that the difference of the 2 values was zero, whereas the alternative was that they differed significantly between them. A chi-square test was performed to evaluate the total incidence of AEs in the 3 groups. The data analysis was performed using the IBM SPSS Statistics v.22 by a professional statistician.

Results

Table 1

Patient demographics and baseline disease severity

Group A Group B Group C P value
Sample size 100 100 100
Age (y), mean ± SD 55.6 ± 10 56.2 ± 9.8 56.7 ± 9.9 .764
Concomitant condition, n (%)
Diabetes mellitus 21 23 22 .931
Cardiovascular risk factors ∗ 67 68 66 .969
Baseline ED severity, n (%)
Mild ED (IIEF-EF score 18–25) 41 38 40 .696
Moderate ED (IIEF-EF score 11–17) 35 37 35 .772
Severe ED (IIEF-EF score 0–10) 24 25 25 .881
Baseline IIEF-EF score, mean ± SD 15 ± 7 14.8 ± 6.9 14.9 ± 7.1 .995
SEP question 3 (% yes) 43 41 42 .974

ED = erectile dysfunction; IIEF-EF = International Index of Erectile Function-erectile function; SD = standard deviation; SEP = Sexual Encounter Profile.

Table 2

IIEF-EF baseline (mean ± SD) IIEF-EF after treatment (mean ± SD) Mean IIEF-EF variation after treatment P value (Student’s t-test) SEP3 (% yes) baseline SEP3 (% yes) after treatment P value (test z)
Overall
Group A (L-arginine) 15 ± 7 18.1 ± 9.2 +3.1 .0089 43 (43/100) 54 (54/100) .0007
Group B (tadalafil) 14.8 ± 6.9 20.8 ± 7.3 +6 41 (41/100) 62.6 (62/99)
Group C (L arginine + tadalafil) 14.9 ± 7.1 22 ± 7.5 +7.1 42 (42/100) 63 (63/100)
Mild ED (IIEF-EF score 18–25)
Group A (L-arginine) 22.1 ± 2.2 27.5 ± 2.3 +5.4 82.9 (34/41) 97.5 (40/41) .0124
Group B (tadalafil) 22.1 ± 2.2 27.8 ± 2 +5.7 84.2 (32/38) 100 (38/38) .0122
Group C (L arginine + tadalafil) 22.2 ± 2.2 29.3 ± 0.9 +7.1 85 (34/40) 100 (40/40) .0123
Moderate ED (IIEF-EF score 11–17)
Group A (L-arginine) 13.5 ± 1.9 16 ± 3.1 +2.5 .0001 25.7 (9/35) 40 (14/35) .023
Group B (tadalafil) 13.8 ± 2 20.5 ± 2.2 +6.7 24.3 (9/37) 56.7 (21/37)
Group C (L arginine + tadalafil) 13.7 ± 2 20.9 ± 3.3 +7.2 22.9 (8/35) 60 (21/35)
Severe ED (IIEF-EF score 0–10)
Group A (L-arginine) 5.1 ± 2.2 5.2 ± 2.3 +0.1 .4966 0 (0/24) 0 (0/24) ND
Group B (tadalafil) 5.3 ± 2.4 10.2 ± 4.2 +4.9 0 (0/25) 12.5 (3/24) .0829
Group C (L arginine + tadalafil) 5.2 ± 2.3 11.8 ± 3.8 +6.6 0 (0/25) 8 (2/25) .1614
Test F – P value Scheffè LSD Bonferroni
A vs B A vs C B vs C A vs B A vs C B vs C A vs B A vs C B vs C
Overall
Mild ∗ 0.706 ∗ 0.4051 ∗ NS
Moderate ∗ 0.4941 ∗ 0.2361 ∗ 0.7082
Severe 0.0031 0.0011 0.0021

ED = erectile dysfunction; IIEF-EF = International Index of Erectile Function-erectile function; SD = standard deviation; SEP = Sexual Encounter Profile.

∗ There was not significant statistical difference between group A and group B in the mild-ED population and between group B and group C in the moderate ED

The type and the incidence of AEs are illustrated in Table 3 . Overall, we report a total of 11, 53, and 67 cases of AEs in group A, B, and C, respectively. The most common AEs were insomnia in the arginine group with a rate of 5% and dyspepsia in both group B and C reported in the 11% and in the 14% of the survey, respectively.

Table 3

Treatment-emergent adverese events (TEAEs)

TEAE (MedDRA preferred term) Group A (L-Arginine) Group B (tadalafil) Group C (L arginine + tadalafil) P value (chi-square test)
Headache 2 8 11
Nasal congestion 0 5 6
Back pain 0 7 6
Dyspepsia 2 11 14
Influenza 0 2 1
Myalgia 0 8 9
Upper respiratory tract infection 0 1 0
Sinusitis 0 1 0
Bronchitis 0 1 0
Cough 0 1 2
Insomnia 5 0 7
flushing 2 5 7
Dizziness 0 3 4
TOTAL OF ADVERSE EVENTS REPORTED 11 53 67

MedDRA = Medical Dictionary for Regulatory Activities.

Discussion

The objective of the present prospective, randomized, multicenter study was to evaluate the effectiveness and tolerability of tadalafil 5 mg and L-arginine 2.5 gm in monotherapy and combination therapy in patients affected by various grades of ED. Although in the official medical literature are present several papers concerning those 2 molecules, to the best of our knowledge, this is the first study investigating their conceivable synergistic effects in a concomitant subscription protocol. Furthermore, this is the first study that compared head to head, directly, and prospectively the effectiveness of L-arginine, tadalafil, and a combination of both substances. This is moreover the first clinical trial evaluating the efficacy of L-arginine in monotherapy in relation to ED severity, including patients affected by severe ED.

L-arginine has been prescribed for ED by uroandrologists worldwide for at least 25 years, since the first article appeared in the far 1994.15 Recently, the interest about this semiessential amino acid increased significantly for the publication of the first systematic review and meta-analysis on its efficacy and safety in monotherapy or combined to other supplements.11 This review led by Chang Rhim et al11 concluded that L-arginine, compared with placebo or no treatment, improves ED of mild to moderate severity and that its subscription for ED is logical because it represents the only physiological substance for NOS.16 Arginine was demonstrated to be an attractive alternative for patients with mild to moderate ED for several reasons. First, arginine is more psychologically accepted because it is perceived as a nutrient rather than a drug. Moreover, arginine was found to exert synergistic effects when administered concomitantly with other supplements such as pycnogenol, yohimbine, adenosine, propionyl-L-carnitine, and niacin.17, 18, 19, 20 The minimal dosage of arginine that was showed to be effective was 2.5 grams, since Klotz et al21 failed to demonstrate significant benefits provided by this supplement administering it at a dose of 500 mg 3 times per day. When arginine was prescribed concomitantly with other substances, the combination worked synergistically determining even greater improvements. However, surprisingly, L-arginine was never investigated in combination with PDE5is, although this class of drugs represents the official first-line therapy for ED. Shirai et al22 reported encouraging results with the combination therapy of citrulline, a precursor of arginine, administered together with PDE5is in a population of patients with ED complaining of unsatisfied efficacy from on-demand use of PDE5is alone. However, this study had some limitations: it did not include patients with ED taking tadalafil once daily (the oral therapy used in the present study), did not include L-citrulline in monotherapy, had a duration of treatment of only 1 month, and the sample size was small. The unique study found in literature in which arginine and tadalafil were evaluated in combination treatment was a Turkish study reporting protective effect of this therapy against ischemia/reperfusion injury for both the testes after unilateral testis torsion in rats.23 Another fundamental aspect to underline, reported in the same review performed by Chang Rhim,11 is that arginine was reported to have a very high safety profile because only 2% of patients treated with this supplement experienced AEs, none of them severe. The safety of arginine was demonstrated even at the highest dosage of 8 grams, as reported by Neuzillet et al.18 The tolerability of arginine is in stark contrast with AEs determined by PDE5is because nearly half of the men treated with sildenafil reported at least one adverse reaction.24 The rational for the use of arginine in patients with ED was demonstrated by Barassi et al,25 who showed that a significant proportion of patients affected by ED, especially of arteriogenic etiology, have a low arginine or citrulline level. Those authors suggested that arginine or other amino acids (citrulline, ornithine) that can increase the serum arginine level can improve ED. Therefore, for all the reasons explained, arginine has been proposed as an alternative for patients who had already experienced AEs with PDEis. In the present study, L-arginine was administered daily in monotherapy at the minimal effective dosage of 2.5 grams in the remarkable survey of 100 men affected by ED of various grade of severity. Arginine was confirmed to be an effective therapy for individuals affected by mild and moderate ED determining a statistic significant improvement (P ≤ .001) in the mean IIEF-EF score of 5.4 and 2.5 points, respectively. Moreover, the safety profile of arginine was confirmed even in our study because all 100 patients treated with this supplement concluded the therapy reporting none or insignificant adverse reactions. It is noteworthy to underline that in the mild-ED population, Arginine had effects comparable with tadalafil 5 mg because no significant differences were found between the 2 substances in terms of the IIEF-EF score. Furthermore, individuals treated with L-arginine reported a lower incidence of AEs than men who received tadalafil 5 mg and/or combination therapy ( Table 3 ). Based on those data, we suggest prescribing L-arginine as an equally effective, cheaper, and safer alternative to tadalafil 5 mg in patients affected by mild ED. On the other hand, in this study, arginine failed to show benefits in the severe-ED population.

In a review of 6 randomized multicenter trial including 1913 men with ED, tadalafil 5 mg once daily was showed to be effective in a variety of relevant patient subpopulations.5 In particular, tadalafil 5 mg once daily was effective in almost all causes of ED, independent of severity (mild, moderate, and/or severe) and etiology. Tadalafil 5 mg once daily presents an ideal pharmacokinetic profile for chronic dosing because it is has a long half-life of 17.5 hours, and its steady-state blood concentrations are achieved within 5 days permitting an exposure to about 1.6 times higher than after a single dose.26 The steady-state drug serum concentrations obtained through a daily tadalafil 5 mg regimen are constant and free from wide fluctuations. Thanks to its favorable pharmokinetic features, tadalafil 5 mg is currently the unique PDE5i, officially approved for daily therapy of ED. Several studies concerning patient preference for PDE5is have remarked the importance that men give to the possibility to obtain a satisfying erection several hours after pill intake: long half-life of PDE5i such as tadalafil was preferred to sildenafil by most patients.4 The longer half-life of tadalafil is a quite crucial pharmacologic feature in order to restore the spontaneity and to free patients from the slavery to be forced to plan their sexual life. Moreover, there are strong data demonstrating that a daily assumption of PDE5is can be potentially effective in improving organic ED acting at the level of vascular endothelium by increasing cyclic guanosine monophosphate concentrations.4 Thus, based on its specific pharmacokinetic features, we considered tadalafil 5 mg once daily the ideal PDE5i protocol to be tested in combination with L-arginine in a daily therapeutic regimen to exert synergistic effects. In our study, when administered in monotherapy, daily Tadalafil 5 mg was confirmed to be a safe and effective treatment in all types of ED severity, providing a statistic significant amelioration in the mean IIEF-EF score of 6 points in overall population and of 5.7, 6.7, and 4.9 points in mild, moderate, and severe-ED population, respectively ( Table 2 ). Daily tadalafil 5 mg monotherapy was safe and free from important adverse reactions because all patients except one included in the group B accomplished treatment. Considering the most important issue evaluated in the present study, we demonstrated that the combination therapy with both tadalafil 5 mg and arginine 2.5 grams once a day was superior to monotherapies alone in overall population and in the mild and severe ED. In the moderate ED group, the combination therapy exerted a small but not significant increase of 0.5 points in the mean IIEF-EF score. Our initial hypothesis was confirmed in our prospective, randomized, multicenter study including 300 patients: combination therapy with tadalafil plus L-arginine worked synergistically determining greater improvements than monotherapy in the IIEF-EF score ( Table 2 ). The greater efficacy of combination therapy is probably determined by the enhancement of NO synthase activity caused by the chronic administration of tadalafil 5 mg in the presence of a greater concentration of a NO source for the concomitant administration of a sufficient dosage of L-arginine. The synergistic effects of the combination therapy are demonstrated even by the greater incidence of AEs in the group C. However, it is remarkable that even if the safety profile was lower than in the other 2 groups, all 100 patients included in the combination group completed the treatment. We believe that the findings of the present study provide a further demonstration for the importance of “tailored therapy” in ED: in patients affected by mild ED can be prescribed the only arginine, tadalafil monotherapy that can be sufficient for moderate ED, whereas in cases of severe ED, combination therapy is the most suitable option.

In our opinion, this study could open very promising scenarios for future researches. First of all, L-arginine can be administered even with other PDE5is such as sildenafil, vardenafil, and avanafil. In particular, we suggest studies evaluating stronger PDEis such as sildenafil or vardenafil in combination with L-arginine. Those synergistic treatments could be effective in the severe ED, but they could determine a greater incidence of adverse reactions, especially if a high drug dosage is prescribed (eg, sildenafil 100 mg or vardenafil 20 mg). Our study presents the limitation of a short follow-up because the duration of the protocol was just 3 months. It is conceivable that longer courses of this combination therapy could exert even greater improvements. We contemplate that a long-course chronic PDE5 inhibition in the presence of a greater arginine blood concentration could potentially provide more enduring improvements of endothelial dysfunctions responsible for ED. The vascular effects exerted by this chronic combination therapy might be responsible for a definitive improvement in erectile function and return to spontaneous erections as suggested by other studies evaluating chronic tadalafil alone.27 , 28 This new therapeutic approach is in our opinion very promising and could lead to scenarios beyond the palliation of ED. It is conceivable that, in a not quite remote future, this very common disease affecting millions of men worldwide will be curable. Under this point of view, appears rational to use the daily combination therapy tadalafil 5 mg plus L-arginine 2.5 grams in more comprehensive recovery program of erectile function. In particular, we suggest future researches in which this treatment could be prescribed concomitantly with low-intensity extracorporeal shock wave therapy, platelet-rich plasma injections, and/or vacuum erection devices in the effort to maximize the neoangiogenis and revascularization process.

We admit that our finding can be limited by the absence of a placebo group. Unfortunately, the medications prescribed in the present study are available in different formulations: tadalafil in pills, whereas L-arginine in powder for oral suspension. For this reason, it was not possible to include a placebo arm or to provide blinding to the study. We encourage randomized, placebo-controlled studies to confirm our results.

Conclusions

In the mild-ED population, arginine had effects comparable with tadalafil 5 mg with a lower incidence of AEs. Arginine failed to show benefits in severe ED but was effective in moderate ED. Combination therapy with both tadalafil 5 mg and arginine 2.5 grams once a day was superior to monotherapies alone in overall population and in mild and severe ED.

Cialis

This is a summary of the European public assessment report (EPAR). It explains how the Committee for Medicinal Products for Human Use (CHMP) assessed the studies performed, to reach its recommendations on how to use the medicine.

If you need more information about your medical condition or your treatment, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist. If you want more information on the basis of the CHMP recommendations, read the scientific discussion (also part of the EPAR).

Cialis is a medicine containing the active substance tadalafil. It is available as tablets (2.5, 5, 10 and 20 mg).

Cialis is used to treat men with erectile dysfunction (sometimes called impotence) when they cannot get, or keep, a hard penis (erection) sufficient for satisfactory sexual activity. For Cialis to be effective in this condition, sexual stimulation is required.

Cialis can also be used in men to treat the signs and symptoms of benign prostatic hyperplasia (enlarged prostate gland that is not cancerous), which involve problems with the flow of urine.

The medicine can only be obtained with a prescription.

For treating erectile dysfunction, the recommended dose of Cialis is 10 mg taken ‘on demand’ at least 30 minutes before sexual activity. The dose may be increased to 20 mg for men who do not respond to the 10 mg dose. The maximum recommended dosing frequency is once per day, but continuous daily use of 10 or 20 mg Cialis is not recommended. Cialis can be used at a lower dose once a day in men who intend to use it frequently (twice a week or more), based on the doctor’s judgement. The dose is 5 mg once a day, but can be lowered to 2.5 mg once a day depending on how well it is tolerated. The medicine should be taken around the same time every day and the appropriateness of the once-a-day dosing should be re-assessed regularly.

For treating men with benign prostatic hyperplasia, or men with both benign prostatic hyperplasia and erectile dysfunction, the recommended dose is 5 mg once a day.

Patients with severe liver problems or kidney problems should not take more than 10 mg in one dose. Once-a-day dosing is not recommended in patients with severe kidney problems, and should only be prescribed to patients with liver problems after a careful evaluation of the benefits and risks of taking the medicine.

The active substance of Cialis, tadalafil, belongs to a group of medicines called ‘phosphodiesterase type 5 (PDE5) inhibitors’. It works by blocking the phosphodiesterase enzyme, which normally breaks down a substance known as cyclic guanosine monophosphate (cGMP). During normal sexual stimulation, cGMP is produced in the penis, where it causes the muscle in the spongy tissue of the penis (the corpora cavernosa) to relax, allowing the flow of blood into the corpora, producing the erection. By blocking the breakdown of cGMP, Cialis restores erectile function. However, sexual stimulation is still needed. By blocking the phosphodiesterase enzyme and preventing the breakdown of cGMP, Cialis also improves the blood flow to, and relaxes the muscles of, the prostate and bladder. This may reduce the problems with the flow of urine which are symptoms of benign prostatic hyperplasia.

Cialis, when taken ‘on demand’ before sexual activity, has been studied in six main studies including 1,328 patients with erectile dysfunction. One of these studies contained only diabetic men. Once-a-day dosing of Cialis was studied in three further studies lasting 12 to 24 weeks and involving a total of 853 patients. In all studies, the effects of Cialis were compared with those of placebo (a dummy treatment), and the main measure of effectiveness was the ability to get and maintain an erection. This was recorded in two questionnaires completed at home.

Cialis has also been studied in patients with benign prostatic hyperplasia. Four main studies comparing Cialis with placebo were carried out in 1,500 patients with the condition, including some who also had erectile dysfunction. The main measure of effectiveness was the improvement in symptoms after 12 weeks.

Cialis was significantly more effective than placebo in all studies in erectile dysfunction. For one of the questionnaires, where the maximum score is 30, patients who recorded scores of about 15 before treatment, recorded scores of 22.6 or 25 after receiving Cialis 10 mg or 20 mg, respectively. Overall, in the studies of general populations, 81% of patients reported that Cialis ‘on demand’ improved their erections as compared to 35% of those taking placebo. Patients taking Cialis once a day at doses of 2.5 or 5 mg also reported improved erections compared with those taking placebo.

Cialis given at a dose of 5 mg was also more effective than placebo in all the studies in patients with benign prostatic hyperplasia, with the results showing a significant improvement in symptoms after 12 weeks compared with placebo.

The most common side effects with Cialis are headache, dyspepsia (indigestion), back pain and myalgia (muscle pain), which are more common at higher doses. For the full list of all side effects reported with Cialis, see the package leaflet.

Cialis must not be used where sexual activity is inadvisable (e.g. in men with heart disease). It must also not be taken by patients who have ever had loss of vision because of a problem with blood flow to the nerve in the eye (non-arteritic anterior ischemic optic neuropathy, NAION). Cialis must not be taken with nitrates (a type of medicine used for angina) or medicines of the class ‘guanylate cyclase stimulators’ such as riociguat (a medicine for high blood pressure in the vessels supplying the lungs, known as pulmonary hypertension). A doctor should consider the potential risks of sexual activity in men who have cardiovascular disease. Because Cialis has not been studied in patients who have had a heart attack within the last three months or a stroke within the last six months, or those who have high blood pressure or heart disorders (irregular heart beat), these men should not use the medicine. For the full list of restrictions, see the package leaflet.

The CHMP decided that Cialis’s benefits are greater than its risks and recommended that it be given marketing authorisation.

A risk management plan has been developed to ensure that Cialis is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Cialis, including the appropriate precautions to be followed by healthcare professionals and patients.

The European Commission granted a marketing authorisation valid throughout the European Union for Cialis on 12 November 2002.

For more information about treatment with Cialis, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

Short- and long-term follow-up results of daily 5-mg tadalafil as a treatment for erectile dysfunction and premature ejaculation

To evaluate the safety and effectiveness of daily 5-mg tadalafil treatment for men who have erectile dysfunction (ED) and premature ejaculation (PE), and to assess the long-term follow-up for ED and PE improvement persistence years after the cessation of medication.

Patients and Methods

A prospective, single-blind, randomised study included 160 patients with ED and PE. All were evaluated using the International Index of Erectile Function (IIEF-5) questionnaire to evaluate ED and intravaginal ejaculatory latency time (IELT) for PE. Patients were subdivided into two equal groups. Group I (80 patients) treated with daily 5-mg tadalafil for 3 months, and Group II (80 patients) treated with a placebo for the same period. After 3 months of treatment and 2 years later after cessation of tadalafil, all patients were assessed for ED and PE.

Results

The mean (SD) IELT and IIEF-5 score pre-treatment were 37 (11.24) s and 13.2 (4.2) for Group I, while in Group II they were 35.98 (10.8) s and 13.12 (4.11), respectively. After 3 months of treatment, the mean (SD) IELT in Group I showed a highly significant improvement from 37 (11.24) s to 120.5 (47.37) s (P < 0.001) but Group II showed no significant improvement from baseline to [39.43 (13.6) s; P > 0.05]. For the IIEF-5 score, there was a highly significant improvement from baseline to 20.45 (4.5) in Group I (P < 0.001), while there was no significant difference in Group II from baseline to [15 (4.84); P > 0.05]. At 2 years after cessation of tadalafil, there was statistically significant improvement in the IELT and IIEF-5 from baseline to endpoint .

Conclusion

Oral daily 5-mg tadalafil was effective, tolerable, and safe treatment for patients with ED and PE. Long-term follow-up at 2 years confirmed the persistence of a significant improvement for both ED and PE.

Abbreviations: ED: erectile dysfunction; IIEF-5: five-item version of the International Index of Erectile Function questionnaire; IELT: intravaginal ejaculatory latency time; OAD: once-daily; PDE5i: phosphodiesterase-5 inhibitors; PE: premature ejaculation; PRN: pro re nata

Introduction

Erectile dysfunction (ED) and premature ejaculation (PE) are the most common sexual dysfunctions with a prevalence of ~30% and ~20%, respectively [ 1 , 2 ]. ED is a failure to accomplish and maintain an adequate erection to reach satisfaction with sexual intercourse for the last 6 months, while PE is defined as an early ejaculation within ~1 min with minimal sexual excitation just after intravaginal penetration with involuntary control that has occurred for ≥6 months in all or almost all sexual activities, leading to anxiety and depression [ 3 ].

Sexual dysfunction includes ejaculatory and orgasmic disorders, ejaculatory disorders include PE and retarded ejaculation (RE), but orgasmic disorders include anorgasmia and hypo-orgasmia. PE is classified into primary or lifelong and secondary or acquired [ 3 ]. Organic factors are the commonest predictors for acquired PE, such as prostatitis [ 4 ] and endocrine disorders [ 5 , 6 ]. Still, routine hormonal testing should only be directed to the patient’s complaints and risk factors with specific findings from history or physical examination [ 7 ].

Every man with PE should be adequately screened for ED, and where present, this should be addressed first. Men with ED can have performance anxiety, which may also favour PE. Accordingly, treating men with ED with ED medications improves erections and ejaculatory latency times (ELTs) [ 7 , 8 ].

PE co-exists with ED in ~30% of patients, mainly secondary PE. However, the specific phenotype of ED-PE men has never been systematically investigated. The five-item version of the International Index of Erectile Function (IIEF-5) questionnaire and intravaginal ELT (IELT) is used to evaluate ED and PE, respectively. The IELT has higher sensitivity and specificity for the evaluation of PE [ 9 ].

There are many modalities for PE treatment, the most commonly used are behavioural and pharmacological therapy, but behavioural therapy is inefficient for many couples. Although many drugs are used for PE, serotonin reuptake inhibitors are the most common drugs used in PE. Other medications like topical anaesthesia or opioid agonists, like tramadol, are less commonly used [ 10 ].

Tadalafil with once-daily (OAD) and on-demand [pro re nata (PRN)] dose regimens is sufficient for treating ED. Other studies reported that the tadalafil OAD dose regimen is better, and more sexual satisfaction occurred than PRN [ 11 , 12 ]. Tadalafil, which is commonly used in the treatment of ED, has been recently investigated in some studies for treating PE, and most of these studies reported a significant improvement [ 13–15 ]. There were no data in the literature about long-term follow-up results of tadalafil on the improvement of PE.

The present study evaluated the efficacy of daily 5-mg tadalafil treatment vs placebo for 3 months on the erectile function (assessed using the IIEF-5) and ejaculation time (IELT) in patients with ED and PE. In addition, we investigated whether there was a significant improvement in the IIEF-5 and IELT after the stoppage of tadalafil for a long time.

Patients and methods

A prospective, single-blind, randomised study comparing the safety and efficacy of 5-mg tadalafil continuous daily dosing for 3 months compared with placebo for ED with PE and assessment of persistence of improvement after 2 years from the cessation of tadalafil.

This study was conducted on 160 patients attending the urology outpatient clinic, Benha University Hospital, and Al-Azhar University Hospital from April 2018 to April 2019, including men aged 18–65 years who had ED and lifelong PE for the last 6 months of a continuous marriage relationship.

We excluded from our study patients with a neurogenic disorder, parkinsonism, diabetes mellitus, active Urinary tract infection (UTI), chronic prostatitis, chronic renal failure, Peyronie’s disease, and endocrine disorders, including low testosterone, hyperprolactinaemia, and thyroid dysfunction, patients taking medications for PE and drugs affecting erectile function.

Written informed consent was obtained from all patients enrolled in this study, which the local ethics committee approved.

Full medical and sexual history was taken with the history of current medications, a complete physical and genital examination was performed, and all patients were evaluated using the IIEF-5 to evaluate ED and IELT for PE [ 16 ] before and after treatment and at the end of the 2-year follow up.

The IIEF is a multidimensional validated questionnaire including 15 questions in the five domains of sexual function (erectile and orgasmic functions, sexual desire, satisfaction with intercourse, and overall sexual satisfaction). More recently, to simplify the IIEF, an abridged five-items version the IIEF-5 has been used as a diagnostic tool for ED and evaluation of treatment. It consists of only five questions, and each IIEF-5 item is scored on a 5-point ordinal scale where lower values represent an impaired sexual function. According to this scale, ED is classified into three grades based on IIEF-5 scores: severe ED (score: 1–7), moderate ED (8–11), and mild ED (12–21) [ 17 ].

The IELT was defined as the time from intravaginal intromission to intravaginal ejaculation. Female partners were provided with a stopwatch and instructions on how to record and measure the IELT. It can be used as an integrated measurement of the partners, and that it was a simple and objective screening indicator for diagnosing self-reporting PE [ 18 ].

Statistical analysis

The collected data were revised, organised, tabulated, and statistically analysed using the Statistical Package for the Social Sciences (SPSS®) version 25.0 (IBM Corp., Armonk, NY, USA). Data are presented as the mean ± standard deviation (SD); Continuous variables in comparable groups were compared by the Student’s t-test (two-tailed). In the intention-to-treat (ITT) analysis, all randomised patients were included in their original group irrespective of their compliance with treatment or loss to follow-up. Patients who were lost to follow-up were considered as a failure to treat. The level of significance was accepted for P < 0.05.

Results

Both groups were comparable for age, weight, and height ( Table 1 ). At the end of 3 months, the mean (SD) IELT in Group I showed a highly significant improvement from 37 (11.24) to 120.5 (47.37) s (P < 0.001). While in Group II, the mean (SD) IELT showed no significant improvement from baseline at 35.98 (10.8) to endpoint at 39.43 (13.6) s (P > 0.05).

Short- and long-term follow-up results of daily 5-mg tadalafil as a treatment for erectile dysfunction and premature ejaculation

Cialis 5 Mg 28 Comp

Cialis is a latest medicine for treatment of disturbances of erection at men. Sialis’s feature is its high-speed performance (30 minutes) and a long-term effect (up to 36 hours). In this regard you can choose the moment which is most suitable for sexual intercourse, having accepted a drug in advance. It is possible to take Sialis in the morning and to be ready even next day. Active ingredient – Tadalafil, the recommended dosage – 20 mg.

Tadalafil contains the same active ingredient as Cialis (tadalafil) and is a cheaper, reliable ED treatment that lasts up to 36hrs.

Cialis Oral Jelly is a new form of medcine which is so popular among a great number of men, a wonderful drug for quick improvement of potentiality and, as a result, a longer and more sensual sexual intercourse. It has the gel form. It is made in wide assortment of pleasant tastes, everyone will find what he likes. It is possible not to wash down the medicine, to dissolve it in a drink, but not in a strong beverage. And its action is about 36 hours!

Cialis Oral Jelly (Orange) – a new formula of Cialis which you can have, without washing down with water. Against background of ordinary drug it differs in increased influence speed. It is prescribed for improvement of sexual endurance of men during intimate proximity. It simplifies the excitative process of penis and strengthens erection. Noticeably increases duration of sexual intercourse. Besides, the drug possesses a pleasant orange flavor.

Tadalafil Oral Strips are based on the Tadalafil 20 mg, the active component that provides the 36 hours effect.

Cialis Professional – effective tablets for improvement of erection. They begin to work in 15 minutes from the moment of taking and actions for 36 hours. They can cause not less than 10, but no more than 16 erections. The medicine increases duration of sexual intercourse. The tablets are successfully used for reduction of time for recovery of erection after ejaculation.

Cialis Soft Flavored – an effective drug intended for fight against erectile dysfunction. It comes in the form of tablets fast-disintegrating, sublingual. It is produced by Sunrise Remedies pharma-company. Drug is convenient and pleasant to use: it has a pleasant fruit taste and at the same time it is quickly absorbed into the blood stream, beginning to work in 20 minutes.

Cialis Soft Tabs differs from a usual tablet of Cialis in the fact that its action comes quicker. Cialis Soft is chewed and dissolved under a tongue that allows to reach a required effect in 10-15 minutes. Important. Cialis Soft is compatible to alcohol and greasy food!

Cialis Super Active is a generic drug, against erectile dysfunction, containing 20 mg of tadalafil. The tablets in this series have a gel inside. This form allows the active substance, Tadalafil, to immediately enter the blood, thus providing an immediate effect. The result from the Cialis Super Active tablets appears after 5 minutes! The action lasts for two days. The drug is safe and has virtually no contraindications.

Cialis with Dapoxetine a combination of 2 ED preparations. Thanks to the complex solution combining the two most active elements, Tadalafil plus Dapoxetine, this remedy eliminates several problems associated with poor male potency: a flaccid erection and too early ejaculation.

Brand Cialis improves erection and helps to achieve a successful sexual intercourse. It is the original medication, intended for use in adult men, who have problems with achieving and maintaining an erection. The pills start acting in 30 to 60 minutes. You can benefit from their effects for up to 36 hours. Therefore, you can take the pills on Saturday evening and enjoy a wonderful weekend, full of sex and pleasant emotions both for you and your partner. The active substance is Tadalafil.

Brand Levitra – a drug from Bayer, with a basic chemical called Vardenafil, is an improved remedy for treating erectile difficulties. Operates approximately within 6-8 hours, so a man may be ready to perform sexually the whole night.

ED Trial Pack (2 Viagra + 2 Cialis + 2 Levitra) – a trial set consists of six tablets, for those who want to understand what medicine is better for him. Includes 6 tablets (by 2 pсs.): Viagra, Cialis and Levitra. It can be taken by people older than 18 years, in case of problems in private life related to fatigue, stress, sleep debt, slow-moving way of life and abuse of addictions.

Female Cialis – Cialis for women – the drug, intended for strengthening of sexual feelings at women who feel discomfort during a sexual intercourse. It causes a high-level excitation in 10-15 minutes after taking of a tablet and keeps efficiency within 36 hours. The drug works due to natural excitement of reproductive system, reacts at tactile proximity. Increases blood circulation of small pelvis, thereby improves secretion of vulval muscles. Increases release of lubricant at sex. Sensitivity of erogenous zones improves.

Kamagra – a pharmaceutical remedy for the readiness of a male sexual organ for a sex, provided by the generics maker named Ajanta, perceptibly balances the male aplomb and is one of the best replacements of Viagra.

Levitra Oral Jelly – a medicine with high performance of libido recovering and potentiality raising at men. The drug is produced by the Indian medical concern Sunrise Remedies. Active agent Vardenafil is the cornerstone of medicine. Its concentration is the same as at Levitra, 20mg but Levitra Oral Jelly has a pleasant taste and you shouldn’t wash it down with water. All this makes the drug very popular among consumers.

Premature ejaculation (PE) is a distressing male sexual dysfunction that can be present from the first sexual encounter or can develop later in life. Men with premature ejaculation appear to go through the same process of ejaculation as other men, but it happens more quickly and with a reduced feeling of control.

Propecia – an anti-hormonal drug. Used to reduce the size of the prostate gland, to increase the maximum speed of urine outflow, reducing the risk of developing acute urinary retention. The drug also turned out to be effective in the treatment of men’s alopecia.

Tadacip – an Indian brand, whose main chemical element is tadalafil, which is also a principal part of Cialis pills. It’s been created by Cipla Ltd. with a more lucrative cost in comparison to Cialis made by the brand-maker Eli Lilly.

Viagra Oral Jelly – a new formula of the drug Viagra. Sildenafil – 100 mg. It is prescribed for men with a weak potentiality. Helps to recover libido and to improve sexual activity. Accelerates process of excitement of reproductive system. It makes erection brighter. Considerably increases duration of sexual intercourse. Besides, drug has various pleasant tastes, it is convenient to carry in a pocket or in a purse. Hurry to try it!

Viagra Soft Tabs – chewable tablets, containing 100 mg of a sildenafil. Difference of Viagra Software from usual Viagra is that its action begins much quicker. Viagra Software is chewed and easily dissolved under the tongue that allows to receive the result in 10-15 minutes.

Viagra with Duloxetine 100mg – one of the modern developments of physicians in the field of prevention and treatment of early ejaculation and extension of sexual contact. It was first produced in 2010 by Sunrise Remedies under the name Malegra DXT and in 3 years gained authority of doctors and trust of men of various nationalities. This drug contains two powerful active agents: Sildenafil (active ingredient of the drug Viagra) and Duloxetine (active ingredient of the drug Cymbalta). Action of Sildenafil, active agent of the drug Viagra, is known long ago and, most likely, does not need detailed description. Duloxetine-antidepressant with a soft action which is also used for prevention of early ejaculation. The combination of these two components in Malegra DXT allows to reach an excellent effect: to relax and concentrate only on sex, to reach a stable erection and to spend more time with a lady than usually.