The overwhelming success of sildenafil in the management of male erectile dysfunction (ED) encouraged both researchers and the pharmaceutical industry to enforce their endeavors in this special field of medicine. Meanwhile two further PDE-5 inhibitors tadalafil and vardenafil have joined sildenafil. Because they are not really distinguishable from sildenafil in terms of efficacy and side effects, but only from the pharmacokinetic profile, they are now directly competing with this very first protagonist. The erectile dysfunction market continues to be very attractive for pharmaceutical companies and independent researchers, in particular due to the fact that at present only between 15 and 20% of all men suffering from erectile dysfunction are treated. The purpose of the following site is to provide a brief overview of the main sites of the current research dedicated to the pharmacologic treatment of erectile dysfunction (ED).

Centrally Acting Drugs Under Clinical Investigation

After apomorphin SL, a dopamine D1/2 receptor agonist with dominant action on D2, has failed on the European market, due to lack of efficacy and clear inferiority to the phosphodiesterase-5 (PDE-5) inhibitors. The main focus in drug development is now directed to other central neurotransmitters known to be involved in processing erection.

Melanocortin receptor (MCR) agonists

Presently there are five MCRs identified and all five are activated by adrenocorticotropin hormone (ACTH) and four out of five, except MC2R, by alpha-melanocyte stimulating hormone (α-MSH). Of the five MCRs only two (MC3R and MC4R) are expressed in cerebral regions known to be involved in the modulation of erectile function. The origin of both alpha-MSH and ACTH is the pro-opiomelanocortin (POMC) gene, and the biologic effects of these two hormones are mediated via activation of one or more of the five MCRs. All five MCRs use cAMP as the second neurotransmitter mediating the final biologic (physiologic) effects upon their activation.

Melanotan II and its active metabolite PT-141 (Bremelanotide), are cyclic pep tide analogues of α-MSH, targeting four of the five MCRs (not MC2R), which have been under investigation for nearly 10 years for their usefulness in the management of erectile dysfunction. Following the first research studies Melanotan II was investigated both as subcutaneous injection and as intranasal spray.

Recently the results with the intranasal melanocortin receptor agonist PT-141 in an at home, multi-center, double-blind, placebo-controlled parallel-arm study in 271 sildenafil-responsive patients were reported, with improved erections in 66-67% with the 10-20mg dose. As shown in Fig. “Athome efficacy of PT-141, an intranasal MCR-agonist, in 271 sildenafil-responsive patients” there was no dose-dependent efficacy between 10 and 20 mg. In two further Rigiscan studies with a subcutaneous (s.c.) application of PT-141 in doses between four and 10 mg, efficacy was reported even in a small group of patients (n = 25) with a history of inadequate response to 100 mg sildenafil and an HEF-EF-score <17. A first response was seen approximately 37 min after the 10 mg dose. Mean duration of efficacy (definition: >60% penile base rigidity) was 41 min for the 6mg s.c. dose, whereas in another study the mean duration of efficacy after intranasal PT-141 was 26 min (6mg dose) and 54min (20mg dose), respectively, compared to 18.5 min in patients receiving placebo. Co-administration of low doses of intranasal PT-141 (7.5mg) and sildenafil (25mg) in men suffering from erectile dysfunction resulted in an enhanced erectile response.

A major problem with this new MCR agonist may be its side effect profile, with nausea rates up to 36 % after 6mg s.c and 17% after intranasal application. Further drug related side effects >5% were headache (up to 27%), flushing (up to 17%) vomiting (up to 9 %), back-pain (up to 9 %), muscle cramps (up tp 9%), and fatigue (up to 8%).

There is no doubt that this completely new approach with MCR agonists seems to be promising in terms of efficacy, but at present there are some uncertainties regarding their side effect profile.

Centrally Acting Compounds with the Potential for Pharmacotherapy in erectile dysfunction

Positive effects on the erectile mechanism were reported from the following centrally-acting compounds.

Oxytocin

In the rat model oxytocin micro-injections into the nucleus paraventricularis and the medial septum of the hippocampus induced erections, which is not the case if these regions were injured through trauma. In small clinical trials, conducted about 30 years and 10 years ago, oxytocin was able to improve erectile dysfunction in patients with psychogenic etiology. As the patent for oxytocin (syntocinon) was revoked long ago, no pharmaceutical company seems to be interested in investigating the potential of this hormone in psychogenic erectile dysfunction (ED).

Serotonin receptor agonists

Generally speaking, serotonin (5-hydroxytrypta-mine, 5-HT) receptors are attributed inhibitory effects in the erectile mechanism, but the serotonin receptor subtypes 5-HTlc/2A and c are suggested to facilitate both erection in male and female sexual proprioceptive behaviour. There were two 5-HT2C agonists in preclinical or clinical phase I/IIA investigations named RSD 992 and YM 348, with no results being reported so far. The pro-erectile effects of RSD 992 were blocked by the 5 -HT2A/C antagonist ritanserin but not by the 5-HT2A antagonist ketanserin, indicating that the 5 -HT2C receptor is the more important one in facilitating an erectile response.

Glutamate

In the rat model it was shown that hippocampal glutamate receptors are involved in the erectile response. The injection of glutamate subtype receptor agonists such as NMD A, ACPD and AMP A, resulted in multiple episodes of erectile responses.

Hexarelin analogues

Hexarelin, a growth hormone (GH)-releasing hexapeptide, induced erections upon intra-paraventricular injection. In the rat model several hexarelin analogues were able to induce erections after injection into the para ventricular nucleus, which resembled the erections caused by apomorphine.

Peripherally-Acting Drugs Under Clinical Investigation

New PDE-5 inhibitors

DA 8159 is a new PDE-5 inhibitor from a South Korean pharmaceutical company with a selectivity that is similar to sildenafil with a Tmax of 1.0-1.5 h andaT1/2 of ll-13h. This new PDE-5 inhibitor was recently investigated in a large multicenter, double-blind placebo-controlled home trial for 12 weeks, in doses of 100 and 200 mg, in 319 men with erectile dysfunction.

As shown in Fig. “Results (SEP 3) of the multicenter trial with the PDE-5 inhibitor DA 8159 (udenafil); N=319”, the sexual encounter profile 3 rates reached nearly 70%, against only 17% at baseline. Side effects >5 % were flushing and headache.

TA-1790 (avanafil) is also a new PDE-5 inhibitor developed for the treatment of erectile dysfunction (ED). Its pharmacokinetic profile shows a Tmax < 1 h and a T1/2 of about 1 hour. In a phase II A Rigiscan study, doses of 50/100/200 mgTA 1790 were compared to sildenafil 50mg and placebo. Whereas the efficacy (rigidity >60% at penile base) of TA 1790 was superior to sildenafil in a time frame of 20-40 min after application, it was inferior to sildenafil after a time frame of 100-120min. The most commonly observed adverse event was flushing in between four and 11 % of patients. The future will show whether these two PDE-5 inhibitors will be developed up to market approval, and whether these two PDE-5 will have the potential to compete with the three marketed PDE-5 inhibitors.

Topical alprostadil (Alprox ®)

Topical alprostadil (Alprox ®-TD) in doses of 100, 200 and 300 µg was investigated against a placebo in two multicenter pivotal phase 3 trials involving 1732 patients with mild to severe erectile dysfunction. The demographics of the study population showed diabetes in 21%, hypertension in 44%, RRP in 12%, CAD in 21%, and nitrate or alpha-blocker medication in 16%. The sexual encounter profile 3 data obtained after 12 weeks of treatment as shown in Fig. “Results of the two pivotal trials with topical alprostadil (Alprox ® TD)”, indicate a clearly inferior efficacy if compared to PDE-5 inhibitors, whose sexual encounter profile 3 data ranged in the literature between 65 and 75 %. It may be presumed that topical alprostadil may play a role in the future combination treatment strategies if PDE-5 inhibitors only are not able to induce satisfactory responses.

Peripherally-Acting Drugs with the Potential for Pharmacotherapy in erectile dysfunction

S-Nitrosylated alpha-blockers

Nitrosylation of alpha-blockers has been reported both with yohimbine and moxisylyte. The additional nitrosylation has no negative impact on the alpha-

adrenoceptor blocking properties but enhances their erectile-inducing efficacy by the additional NO-donor activities. Although this concept was introduced nearly 10 years ago, no results of clinical studies are reported to date.

Nitric oxide-releasing PDE-5 inhibitors

NCX-911 a novel nitric oxide-releasing PDE-5 inhibitor, turnedouttobe superiorto sildenafil in the rabbit model if there was a lack of endogenous NO. To date no data on clinical trials have been reported.

Guanylate cyclase (GC) activators

Several research groups were focusing in the past couple of years on guanylate cyclase, on the GC-B, a membrane bound enzyme in particular involved in the physiologic process of erection by promoting the cleavage of cGMP from GTP. At least two GC activators, i.e. YC-1 and BAY 41-2272, have shown potential efficacy both in animal models and in vitro experiments with human corpus cavernosum muscle strips. At present no data are available on clinical trials, but based on findings in experiments with diabetic rats it is speculated that GC activators may be more effective in diabetic erectile dysfunction than the common PDE-5 inhibitors. This speculation relies on the observation that endogenous NO release is significantly decreased in diabetes, and that NO-independent GC activators as well as NO-releasing PDE-5 inhibitors may be more useful in diabetic erectile dysfunction.

Rho-kinase inhibitors

A variety of research findings emphasize the role of Rho-kinase in the regulation of the corpus cavernosum smooth muscle tone, i.e. maintaining contraction and thereby preventing erection. It has been shown that Rho-kinase expression and activity is clearly up-regulated, both in diabetes and hypertension and in hypoxemic conditions. In the animal model Rho-kinase inhibitors were able to ameliorate erectile dysfunction. Recent studies performed in hypertensive rats have provided evidence that the combination of PDE-5 inhibitors and Rho kinase inhibitors are superior to the respective mono-therapies, Finally the topical application of the Rho-kinase inhibitor Y-27632 to the rat tunica albuginea resulted in an erectile response.

Conclusions

As briefly described in this site, there are a variety of targets worthy of being considered for the development of pharmaceutical drugs in the indication of male erectile dysfunction, both on the central and the peripheral level. Without any doubt the following couple of years will be exciting in this held.

 

Selections from the book: “Standard Practice in Sexual Medicine”, edited by Hartmut Porst, Jacques Buvat, and The Standards Committee of the International Society for Sexual Medicine, 2006.

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