The first clinical data concerning the efficacy of mirodenafil were reported in 2008 [1]. That multicenter, randomized, double-blind, placebo-controlled study was performed after a 4-week run-in baseline period during which no drug or placebo was offered. Patients were prescribed mirodenafil at fixed doses of 50 or 100 mg for 12 weeks on an 'as-needed' basis. The mean age of all subjects was 52.9 years. At baseline, 3.2% of all subjects had mild ED (scores of 22~25), 29.7% had mild-to-moderate ED (scores of 17~21), 43.2% had moderate ED (scores of 11~16), and 23.9% had severe ED (scores of 1~10). Finally, 215 (96.4%) of the 223 males completed the trial. The primary outcome measure (International Index of Erectile Function [IIEF] question [Q] 3 score) increased by 0.68 from the baseline in the placebo group compared with 1.16 and 1.64 in the mirodenafil 50- and 100-mg groups, respectively. The IIEF Q3 scores of the mirodenafil 50- and 100-mg groups increased by a significantly greater amount than those of the placebo group (p=0.0001 and p<0.0001, respectively).

These results are comparable with those of other PDE5 inhibitors, although no head-to-head comparative studies have been conducted. In the first clinical trial of sildenafil involving males with ED, the IIEF Q3 score increased by 0.1 from the baseline in the placebo group compared with increases of 1.6 and 2.0 in the sildenafil 50- and 100-mg groups, respectively [23]. In the initial results of tadalafil in 179 males with ED (8.9% had mild ED, 37.6% had mild-to-moderate ED, 28.7% had moderate ED, and 24.8% had severe ED), the IIEF Q3 score increased by 0.3 from the baseline in the placebo group compared with increases of 1.0 and 1.3 in the 10- and 25-mg dose groups, respectively [24]. In the first clinical trial of vardenafil involving 580 males with ED (37.5% had moderate ED and 31.9% had severe ED), the IIEF Q3 score increased by 0.2 from the baseline in the placebo group compared with increases of 1.3 and 1.5 in the vardenafil 10- and 20-mg groups, respectively.

A recent meta-analysis reported no major differences in efficacy among the three traditional PDE5 inhibitors (tadalafil, sildenafil, and vardenafil), but further studies of other PDE5 inhibitors (avanafil, lodenafil, udenafil, and mirodenafil) and a comparison of efficacy among the various PDE5 inhibitors are needed because of limitations in the quality and quantity of the currently available evidence [25].

The findings from many epidemiological studies show that ED is associated with chronic diseases such as diabetes mellitus (DM), hypertension, and spinal cord injury [26]. Several studies have shown that PDE5 inhibitors improve ED in males with chronic diseases [27,28,29,30]. However, few studies have been conducted on mirodenafil in this regard despite the general presumption that mirodenafil is also effective for ED in subjects with chronic diseases.

In a study of the pharmacokinetics of mirodenafil in streptozotocin-induced DM rats [31], mirodenafil was detected in the plasma in 5 minutes and was absorbed with a T_max of 15 to 60 minutes in both the control and DM groups. The C_max and total area under the plasma concentration curve from time zero to infinity for mirodenafil in the DM group were also comparable to those in the control group. In a randomized, placebo-controlled clinical trial in patients with diabetes [32], the on-demand dosing of mirodenafil resulted in a significant improvement in erectile function (Table 2), and the drug was safe and well-tolerated irrespective of the baseline severity of DM. However, only a low dose of mirodenafil (50 mg) was used in this trial considering that the maximum dose of a PDE5 inhibitor is generally required in patients with DM [33].

In a study on the pharmacokinetics of mirodenafil in hypertensive rats [34], 16-week-old spontaneously hypertensive rats (SHRs) (an animal model of the chronic phase of essential hypertension) showed significantly greater intravenous AUC and comparable oral AUC of mirodenafil compared with those of the controls. The AUCs of intravenous and oral mirodenafil in 6-week-old SHRs were significantly greater than those in the controls. Additionally, the AUC of oral mirodenafil alone in 16-week-old deoxycorticosterone acetate salt-induced rats (an animal model of secondary hypertension) was significantly smaller than that in the control rats. These results suggest that the pharmacokinetics of mirodenafil may not be affected by essential hypertension itself. However, a more important clinical issue is the relationship between ED and hypertension, and the possible interaction between mirodenafil and antihypertensive drugs. In an experimental study of the effects combining mirodenafil with antihypertensive drugs on the relaxation of rabbits' corpus cavernosum [35], the effect of mirodenafil was significantly enhanced by an angiotensin receptor blocker (losartan), a calcium channel blocker (nifedipine or amlodipine), and an alpha adrenergic blocker (doxazosin or tamsulosin) by >40%, but not by an angiotensin-converting enzyme inhibitor. These results are comparable to those of other PDE5 inhibitors and suggest that mirodenafil, like other PDE5 inhibitors, should be initiated at a lower dose in patients using hypertensive drugs. In a randomized, placebo-controlled clinical trial in patients taking an antihypertensive drug [36], the on-demand dosing of mirodenafil resulted in a significant improvement in erectile function, and the efficacy of mirodenafil seemed to be comparable to that of other PDE5 inhibitors (Table 3). Furthermore, mirodenafil did not show clinically significant long-term changes in hypertension-associated parameters such as blood pressure, heart rate, or electrocardiographic findings. However, a relatively small percentage of patients taking diuretics (14.8%) and a beta adrenergic blocker (25.9%) were enrolled, and the immediate effects of mirodenafil on hypertension-associated parameters were not evaluated.

Several studies suggest that PDE5 inhibitors, particularly sildenafil, in patients with spinal cord injury are first-line therapy for ED [30]. However, it is difficult to distinguish among the PDE5 inhibitors and to counsel individual patients in clinical practice. Only one experimental study on mirodenafil is available in this area. In an acute spinal cord-injured rabbit model, mirodenafil significantly improved erectile function, and its efficacy was greater than that of sildenafil with respect to the peak length of the penile mucosa and the onset time of action [11].

A study of the use of mirodenafil combined with dapoxetine in patients with premature ejaculation (PE) without ED has been published [37]. Mirodenafil combined with dapoxetine showed better results in terms of intravaginal ejaculatory latency time and PE profile index score, and similar treatment-emergent adverse events, compared with those of dapoxetine alone. This was the first randomized, placebo-controlled clinical trial on the use of a PDE5 inhibitor combined with dapoxetine for PE. This result suggests that adding a PDE5 inhibitor to dapoxetine may be more effective and safer than dapoxetine alone.

The efficacy and tolerability of mirodenafil are expected to be comparable to or better than those of other PDE5 inhibitors in patients with ED and a chronic disease because mirodenafil demonstrates higher selectivity toward PDE5 and lower selectivity toward other PDE family members than sildenafil [3]. Moreover, experimental and clinical data show the usefulness of mirodenafil. However, there is insufficient evidence to demonstrate the usefulness of mirodenafil in patients with ED and a chronic disease. Further research is needed to answer this question.

Since 1998, when sildenafil came onto the market, PDE5 inhibitors have been used for ED as first-line treatment [23,38]. Many studies have reported the effectiveness and safety of the daily administration of PDE5 inhibitors [39,40,41,42].

The rationale for daily administration of PDE5 inhibitors to treat ED is based on a report by Eardley et al [43] published in 2004. According to this report, people usually initiate sex within 30 minutes of their intention to do so irrespective of the presence of ED. Another study on females conducted by Fisher et al [44] in 2005 reported that 30% and 34%, respectively, of males and females have sexual intercourse without a schedule. These two studies confirm that the behavior and timing of sexual intercourse between males and females cannot be anticipated and explain the limitation of on-demand PDE5 inhibitor therapy, which needs to be administered prior to sexual intercourse. The unpredictable timing and short lead time for sex may be a rationale for the daily administration of PDE5 inhibitors.

Males with ED mostly want to be able to have sex any time with a spontaneous erection [45]. The ability to have a spontaneous erection is more important for them than sexual intercourse itself. Porst et al [46] reported that daily administration of a PDE5 inhibitor allows patients with ED to obtain spontaneous erections. Daily administration of a PDE5 inhibitor is meaningful because a patient can have spontaneous erections and perform intercourse without having to take a PDE5 inhibitor beforehand.

Daily administration of tadalafil is a method of obtaining a spontaneous erection in patients with ED and allowing them to forget about their disease [46]. The basis of the study was that through daily administration, agents with a comparatively long half-life could remain in the blood at a level higher than the minimally effective concentration. However, Chung et al [42] reported that once daily administration of mirodenafil, which has a T_max of 1.25 hours and a t_1/2 of 2.5 hours [2], improves the sexual function and LUTS of patients.

Konstantinopoulos et al [47] reported that a significant increase in ET-1, nitric oxide (NO), and cGMP is observed in patients with ED when the molecular markers (ET-1, NO, cGMP, thrombomodulin, E-selectin, and vEF) of the endothelial function affecting erectile function were measured after once daily treatment with sildenafil, which has a comparatively short half-life. As a result of animal experiments, the mirodenafil-administration group showed a larger AUC and a higher peak serum concentration of the therapeutic drug than the sildenafil-administration group [6]. As shown in these two studies, the once daily treatment with mirodenafil is expected to improve endothelial function as well as the once daily treatment of sildenafil. Zhao et al [48] reported the efficacy of a once daily udenafil treatment in patients with ED. They found that the daily administration of 50 mg of udenafil had mild side effects and was effective in improving ED. In another study, Zhao et al [49] reported a difference between the blood and tissue concentrations after administering a PDE5 inhibitor prior to transurethral prostatectomy in patients with BPH. In animal experiments, concentrations of mirodenafil in the plasma and the corpus cavernosum were confirmed to be different [6]. On the basis of these results, the effects of the once daily treatment cannot be determined by using the blood concentration of the agent and half-life. A post-antibiotic effect-sub-minimum inhibitory concentration effect is observed in the cases of antibiotic agents. This is the mechanism of delayed cell growth, morphological changes, and increasing post-antibiotic effects even though the level of antibiotic in blood is lower than the minimal inhibitory concentration [50]. This result suggests that PDE5 inhibitors can affect the body at a level lower than the minimally effective concentration. In addition, a once daily treatment with agents having a short half-life can be effective due to pharmacodynamic factors such as drug distribution, bioavailability, and reabsorption [51].

The prevalence of both ED and LUTS associated with BPH increases with age. Clinical evidence shows that ED and LUTS due to BPH have a common pathophysiology [52]. The first-line treatment options for BPH-LUTS include pharmacotherapy with α₁-adrenergic blockers or 5α-reductase inhibitors. The latter are prescribed when there is significant prostatic enlargement. Both types of agents are associated with unwanted side effects, including orthostatic hypotension and dizziness with α₁-adrenergic blockers, decreased libido and ED with 5α-reductase inhibitors, and ED with both [53]. Additionally, α₁-adrenergic blockers can cause anejaculation or retrograde ejaculation, whereas 5α-reductase inhibitors can decrease ejaculate volume. Due to the limitations of current therapy, numerous clinical trials have been conducted to test the potential role of PDE5 inhibitors in BPH-LUTS treatment. Although the exact mechanism of action remains to be clarified, PDE5 inhibitors have shown efficacy in treating LUTS in males with and without ED. These drugs may be considered first-line treatment for males with an ED history. With the advent of an additional class of drugs to treat LUTS, medical therapy can be individualized for ensuring maximum patient benefit. Three studies concerning the use of mirodenafil in LUTS are included in the current literature: two on the combination of mirodenafil with α₁-blockers and one on mirodenafil vs. placebo. The first trial to examine the role of mirodenafil in the treatment of LUTS was a multicenter, open-label prospective study of 121 males with ED [54]. All patients were given α₁-blockers (0.2 mg of tamsulosin or 10 mg of alfuzosin) to treat LUTS/BPH for >3 months before the study commenced, and the patients were then given two oral mirodenafil doses of 100 mg per week to be taken before intercourse. It was emphasized that the patients should take the mirodenafil at least 6 hours after having the α₁-blocker. The participants completed the International Prostate Symptom Score (IPSS)/quality of life (QoL), peak urine flow rate (Q_max), post void residual volume (PVR), and IIEF-5 tests at baseline and again during 4- and 8-week reviews. After 8 weeks of treatment with mirodenafil, there were significant improvements in the IIEF-5 and the IPSS/QoL but not Q_max or PVR. Facial flushing was the most common adverse effect, followed by headache and dizziness. None of the subjects dropped out of the study because of adverse effects. The second study was a multicenter, open-label prospective study that assessed the clinical efficacy and safety of mirodenafil co-administered with an α₁-blocker to patients with both BPH-LUTS and ED [55]. A total of 147 sexually active males with a history of BPH-LUTS and ED for ≥3 months were eligible. Apart from having a personal history of BPH-LUTS and ED, the patients enrolled in this trial had been receiving stable α₁-blocker therapy for at least 4 weeks, although they were not fully satisfied with their current medical treatment. In addition to maintenance α₁-blocker therapy, all patients were prescribed 50 mg of mirodenafil OD after enrollment. The co-primary measures were the IPSS and the IIEF-5, and the key secondary measures were Q_max and PVR volume at baseline and 8 weeks. The IIEF-5 score improved at 8 weeks. The combination of mirodenafil with a α₁-blocker did not significantly improve PVR; however, Q_max improved at 8 weeks. Hot flashes (10.9%) were the most common adverse effect, followed by headache (8.1%). The third was a multicenter, double-blind placebo-controlled trial involving 134 males with ED who were administered mirodenafil [42]. The patients were randomly allocated into two groups. Group 1 (90 patients) received 50 mg of mirodenafil once daily, and group 2 (90 patients) received a placebo daily. IIEF-5, IPSS, Q_max, and PVR were assessed at 4, 8, and 12 weeks after the start of treatment. Of the 180 patients, 71 in group 1 and 63 in group 2 completed the 12-week clinical trial. After 12 weeks of once daily 50 mg of mirodenafil administration, the group 1 patients showed significant improvements in the IIEF-5 scores compared with group 2 patients. Significant improvements in LUTS were observed in the IPSS/QoL and uroflowmetry across the treatment group as secondary efficacy variables compared with those in the placebo group. Headache was the most common adverse effect, followed by facial flushing. The results of three studies concerning the use of mirodenafil in patients with LUTS suggest that mirodenafil significantly improves LUTS and erectile function in males with BPH. Mirodenafil seems to be a treatment option for patients with LUTS secondary to BPH with ED. Further studies are needed to determine the long-term outcomes, and a large-scale study is required for further evaluation of efficacy.