Alprostadil and Erectile Dysfunction

What do you do when the PDE5 Inhibitors and HRT fail you? Some men do not have the “garden variety” erectile dysfunction and need a bigger gun to overcome their issues. Alprostadil can be a real (sex) life saver for many such men. It currently comes in three different forms, which we will discuss below and is also known primarily by three brand names: Vitaros, Muse and Caverject.

There are currently two licensed treatments applied directly to the penis which are intended give an automatic or semi-automatic erection. Caverject is injected and is the more reliable treatment. Muse is a suppository inserted, via a tube, into the end of the penis. I m told the injection isn t as bad as it sounds, but I ve no experience of either. The active ingredient in both is Alprostadil.

A clinical trial by Shabsigh et al evaluated changes in IIEF-EF scores in patients taking Muse and Caverject. Patients with mixed etiologies were recruited for the study. Baseline scores for Q3, Q4, and the EF domain were 1.7, 1.3 and 9.2, respectively. Following treatment with Caverject, mean scores increased to 4.4 and 4.2 for Q3 and Q4, respectively, compared with 3.0 and 2.8 for MUSE. The EF domain score increased to 25.3 for Caverject and 17.3 for MUSE. This suggests an increase in EF score of 8.1 for Muse and a remarkable 15.1 for Caverject.

There should soon be a third Alprostadil treatment available, a cream applied to the head of the penis in small amounts, called Vitaros , developed by Apricus Biosciences. Though Vitaros is described as a cream, the package leaflet shows a liquid being dropped into the tip of the penis, from a pipette (in which Vitaros is supplied). This has clear ease and convenience advantages over injections and suppositories.

Vitaros will need to be stored in a fridge, but can last up to seven days at room temperature. It will be supplied in single dose packs at about 8/dose. A room temperature version is planned.

Vitaros is said to work in around five to fifteen minutes, and the erection-inducing effect may last up to a couple of hours, or until you orgasm. It should work even for psychogenic dysfunction as dopamine-response is less of an issue.

In some ways Vitaros seems ideal: if discretion is important, you just visit the loo before undressing, and you re ready a few minutes later, – assuming it works. And, if you re not invited in , unlike Viagra, you ve not wasted 8.

Vitaros was approved in Canada in 2010, and should be available there through Abbott Laboratories. The current, much postponed, launch date is November 2013. It was approved in Europe in June 2013, and planned launch date in the UK is January 2014.

I know two of the andrologists who will be helping with the launch of Vitaros in the UK. They believe it will be more effective than Muse, but not as effective as Caverject.

Clinical Trial 1

A double-blind placebo-controlled trial, led by Jacques Buvat, was reported to the December 2012 conference of the European Society for Sexual Medicine . A number confusing graphs and charts were provided. One chart indicates that by the 180th day nineteen of twenty patients on a 200mcg dose had increased their IIEF score by 4 or more, and that the average IIEF-EF score, for patients on the 200mcg dose, increased from 13.2 at baseline to 26.4 after six months, which seems remarkable. However 290 patients started the 200mcg trial, after a month the number had reduced to 122, and by six months only 20 patients remained. Presumably those final twenty were amongst the happiest with their results. Therefore the chart doesn t tell you much: only that around 7% of patients achieved, by Day 180, an average IIEF-EF score of 26.4% (no dysfunction). You don t know their baseline score. (Perhaps they started at around 21 and rose an average of 5 or 6 points?)

The patients choosing the 300mcg dose started from a lower baseline score of 10.6, and rose to 20 7 after six months, but their number dropped from 846 at baseline to 119. A dropout rate of 86%.

It seems likely that if, after a few attempts with Vitaros, a patient detects no benefit, that patient is more likely give up, and leave the trial. Only the minority showing a worthwhile improvement will remain, – thus the published figures need to be interpreted with care.

Another chart, for the 200mcg doses, showed 55% penetration success rates at baseline improved to 98% after six months, but you must recall the 93% dropout rate. After one month the dropout rate was 58%, and the 42% of remaining patients increased their penetration success rate to 92%, – so reasonably encouraging. The penetration and maintenance success was up from 32% at baseline to 90% after six months for the twenty remaining patients. (81% success after 30 days for the 122 remaining patients.)

The 300mcg group, whose condition was more severe, fared less well. After the first month the 300mcg patient numbers had reduced only slightly from 846 to 828 and their penetration success rate increased marginally from 50% to 60%.

A chart showing Reasons for Discontinuation indicates that 33% of the 200mcg dose patients withdrew due to protocol violation . 28% left due to investigator decision . 19% left after withdrawing consent. 8% due to adverse effects, 11% unknown or lost to follow up . The principal three reasons could, in effect, be the non-responders choosing to leave.

The difficult to treat placebo group in the trial recorded reduced IIEF scores. The reduction was 0.6 for hypertensives, 1.2 for the diabetics, and 1.7 for those with cardio-vascular problems. Around 40% of the treated difficult to treat group achieved an increase in IIEF-EF score of 4 or more.

The conclusion states that there is good efficacy with 200mcg applications in (only) 25% of patients. But it also states that the 300mcg dose gives clinically significant improvement in up to 80% of patients. Good efficacy must, presumably, mean more than clinically significant . And what does up to really mean?

Vitaros was considered a simple and reasonably effective first choice treatment option.

The trial was due to last a year but the sponsor withdrew funding before the trial was completed.

Clinical Trial 2

A second trial was reported at the American Urological Association annual conference in May 2013. Dr John P. Mulhall, director of the Male Sexual and Reproductive Medicine Program at Memorial Sloan-Kettering Cancer Centre in New York, presented safety and efficacy data from a phase 3 study of Vitaros in 1727 men with ED. Increases in the IIEF-EF score, after twelve weeks, in the 200mcg and the 300 mcg groups were 2.4 and 2.5, which is only similar to that usually reported in the placebo group in such trials. By comparison, in Professor Vardi s shockwave double-blind trial an average 6.7 point increase was reported in the treated group, and 3 in the sham group. However the placebo group in Dr Mulhall s Vitaros trial reported reduced scores, – on average by 0.7. So Dr Mulhall s treated patients had a similar improvement compared to the placebo group as did Professor s Vardi s shockwave patients. (Early clinical trials for Viagra tended to report increased IIEF-EF scores of around 8 to 11.)

51% patients in the 200mcg group reported an improvement in their erections after twelve weeks, with higher baseline scores relating to greater improvements. This doesn t sound impressive, but with longer-term exposure nearly all of the, now only, 1161 subjects (100%, 100%, and 88.2% in each of the 100mcg, 200mcg, and 300mcg dose groups respectively) had an improvement in IIEF-EF score, and more than 90% of the patients reported improvements in their erections. (You have to wonder how up to 10% of patients had an improvement in IIEF-EF scores but no improvement in erections.)

The mean IIEF-EF score also continued to improve after the initial twelve weeks for men choosing the 300 mcg dose level

The report concluded patients repeatedly exposed to Vitaros do not find that safety and efficacy diminishes with longer term use.

Dr. Mulhall also reported a phase 3 study of Vitaros in 325 men who were previously unresponsive to PDE5i. Results showed that Vitaros improved erections in this population and that adverse events were mild to moderate, similar to those seen in the control group, and decreased with repeated exposure.

Observations on the Trials

If Vitaros improves erections in only 51% of men after twelve weeks, but gives improvements in more than 90% of men after longer term use, does that mean changes in the penises occurred? Perhaps the penises became more absorbent? Dr Raheem believes the patients were old, and therefore needed time to understand how best to use the medication. It should be noted that about a third of patients dropped out after twelve weeks, – and those patients are likely to have been the poor responders. Perhaps only those most benefitting from Vitaros were counted in the longer term use category, and so appeared to boost the average increase ion EF scores.

If the Shabsigh et al clinical trial showed increased EF scores with Muse of 8.1, then why did Dr. Mulhall only report an increase of 2.5 with Vitaros? (Perhaps part of the answer is that the Shabsigh trial wasn t placebo controlled.)

Vitaros can, of course, be combined with other therapies, and might be ideal for a man who can eventually achieve a good erection, perhaps with pornography but not with a real-life partner. Vitaros might give such a man that initial boost, and then the natural excitement of intercourse will take over for a satisfactory encounter.

A similar unlicensed substance, named Befar, is available in some countries, and can be ordered online, – however it gets sent from Singapore, and after three days of room temperature it becomes less effective.

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