Table 2. Summary of emerging therapy for ED: peripherally acting agents.

Compound	Type of study	Mechanism of action	Route and dosage of administration	Population studied	Main findings	Date (year)	Author
SLx-2101	Phase IA double-blind, randomized, single dose study	New oral PDE5-I	Oral 5, 10, 20, 40, and 80 mg	Healthy men (n=8)	SLx-2101 was well-tolerated in single doses up to 40 mg.	2006	Prince et al [59]
					Positive effects were shown at 0–6 h post-dose without VSS for 10, 20, 40, and 80 mg doses.
					The common side effects are headache and have been minimal.
Vardenafil ODT	Phase I/III	PDE5-I sublingual dispersal agent	Orodispersal 10 mg	Men of broad age range with ED	Vardenafil ODT has a similar pharmacokinetic profile to vardenafil FCT.	2011	Heinig et al [63]
					Vardenafil ODT has significantly greater bioavailability and was well-tolerated.
Sildenafil ODT	Phase I randomized, open-label, crossover, single-dose study	PDE5-I sublingual dispersal agent	Orodispersal 50 mg	Healthy men (n=36)	Sildenafil ODT without water, was bioequivalent to sildenafil FCT.	2014	Damle et al [64]
					High fat meals reduced the rate of absorption of sildenafil ODT.
Sildenafil ODF		PDE5-I sublingual dispersal agent	Orodispersal 75 mg	Patients with ED (n=139)	Sildenafil ODF had the same safety and effectiveness of the FCT, was better appreciated by patients in overall satisfaction.	2017	Cocci et al [65]
Sildenafil ODF	Phase I	PDE5-I sublingual dispersal agent	Orodispersal equal dosage of FCT 50 mg	Psychogenic ED patients (n=20)	The serum level of ODF increased faster than those of both FCT and ODT.	2018	De toni et al [66]
					ODF showed a lower prevalence of headache compared to FCT and improved pattern of flushing and nasal congestion.
Tadalafil ODF	Phase I open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design	PDE5-I sublingual dispersal agent	Orodispersal equal dosage of FCT 20 mg	Healthy men (n=36)	The pharmacokinetics of the tadalafil ODF formulation was similar to those of the FCT formulation.	2018	Park et al [67]
					Both ODF and FCT formulations were well-tolerated.
L-arginine	Phase II randomized, double-blind, crossover, placebo-controlled comparative clinical trial	NO donors	Oral on demand for 2 wk L-arginine aspartate 8 g+AA 200 mg	ED patients (n=26)	Combination group showed the improvements in EHS and IIEF-scores compared to patients treated with placebo.	2013	Neuzillet et al [74]
					This drug was well-tolerated and there was no severe adverse effect.
L-arginine	Randomized controlled trial	NO donors	Oral sildenafil 50 mg (every other day)+L-arginine 1 g (3 times daily)	Organic ED (combination=30, sildenafil=29)	Combination group improved IIEF-5 score compared to sildenafil alone group.	2020	El-Wakeel et al [75]
MED2005 (GTN)	Phase II randomized, double-blinded, placebo-controlled, crossover trial	NO donors	Topical 0.2% GTN gel	ED patients (n=232)	23% patients showed ≥4 points IIEF-EF increase after treatment vs. 14% after placebo.	2018	Ralph et al [78]
					The onset of erection in 70% of patient was less than 10 min.
					Adverse events were mild headaches and rhinitis.

ED: erectile dysfunction, PDE5-I: phosphodiesterase type 5 inhibitor, VSS: visual sexual stimulation, ODT: oro-dispersible tablets, FCT: film-coated tablets, ODF: oro-dispersal film, NO: nitric oxid, AA: adenosine monophosphate, EHS: erection hardness score, IIEF: international index of erectile function, GTN: glyceryl trinitrate, IIEF-EF: international index of erectile function-erectile function.