Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction


Michael Wyllie, Plethora Solutions Ltd, 4th Floor, 233 High Holborn, London, UK.e-mail:


Erectile dysfunction (ED) is becoming an increasingly common problem and although oral therapies offer first-line treatment for many men, they are contraindicated or ineffective in substantial groups of patients. Intracavernosal injection (ICI) therapy is the most effective nonsurgical treatment for ED and offers an effective alternative to oral therapy. Sufficient arterial blood supply and a functional veno-occlusive mechanism are prerequisites in the attainment and maintenance of a functional erection. Invicorp® (Plethora Solutions, London, UK) is a combination of vasoactive intestinal polypeptide (VIP) 25 µg and phentolamine mesylate 1 or 2 mg for ICI in the management of moderate to severe ED. The two active components have complementary modes of action; VIP has a potent effect on the veno-occlusive mechanism, but little effect on arterial inflow, whereas phentolamine increases arterial blood flow with no effect on the veno-occlusive mechanism. Clinical studies showed that Invicorp is effective in ≥80% of men with ED, including those who have failed to respond to other therapies and, unlike existing intracavernosal therapies, is associated with a very low incidence of penile pain and virtually negligible risk of priapism. We estimate that there are >5.9 million men in the USA alone for whom oral ED drugs are not a viable treatment option, and for whom Invicorp might offer a safe and effective alternative.


erectile dysfunction




intracavernosal injection


vasoactive intestinal polypeptide.


Erectile dysfunction (ED), the persistent inability to attain and maintain an erection adequate to permit satisfactory sexual performance [1], is becoming an increasingly common problem as a result of media attention, the decrease in the stigma of impotence, and subsequently higher sexual expectations in an ageing population.

Oral phosphodiesterase-5 (PDE-5) inhibitors, unless contraindicated, are the usual first-line therapy for ED. However, in a substantial proportion of patients (30%) the effectiveness of PDE-5 inhibitors is minimal, with 46% of patients quitting oral medication, largely due to lack of efficacy [2,3]. In addition, PDE-5 inhibitors are contraindicated in patients taking organic nitrates and nitrites, and need to be prescribed with caution in patients taking α-blockers or at risk of prolongation of the QT interval [4].

Intracavernosal injection (ICI) therapy is the most effective nonsurgical treatment for ED in all causes of erectile failure, and therapies currently include papaverine, α-adrenoreceptor blocking agents such as phentolamine, and prostaglandin E1 (alprostadil). Alprostadil, the most widely used intracavernosal agent, has a response rate of >70%, but produces painful erections in up to 30% of cases [5,6]. Papaverine has a reported efficacy of 54%, but its use is associated with cavernosal fibrosis and an incidence (≈3%) of priapism [6].


The regulation of penile erection is thought to be under neural control [7]. Virag et al.[8] showed that the smooth muscle relaxant papaverine and the α-adrenoreceptor antagonist phentolamine, given by ICI, can be used to induce penile erection in the treatment of ED.

Vasoactive intestinal polypeptide (VIP; International nonproprietary name, aviptadil) is a naturally occurring 28-amino acid neurotransmitter present in the male genital tract [9,10], with a putative role in local nervous control of smooth muscle activity and penile erection [9–11]. It appears that VIP has a specific role in controlling the veno-occlusion resulting from the relaxation of smooth muscle [12]. In addition, VIPergic nerves were found to be depleted in the corpus cavernosum of men with ED and diabetes-related ED [13]. Following the suggestion that a deficiency in VIP might be responsible for ED, several workers investigated the possibility that VIP per se might be an inducing agent for penile erection. A study by Wagner and Gertenberg [14] into the effect of VIP (1 µg−20 µg) in normal men showed that VIP alone induced tumescence but not erection in doses of up to 20 µg.

As an agent for treating ED, the use of low doses of up to l.2 µg of VIP administered intracavernosally was unsuccessful, and even doses up to 60 µg would not induce a useful erection even with visual or tactile stimulation in more severely impaired patients [15,16]. There was also severe facial flushing at doses of 60 µg, and it was concluded that the optimum dose for further investigation would be 30 µg, which equates to 25 µg after adjustment in relation to water and acetate content [14].

The normal erectile process requires there to be both an adequate arterial inflow and an efficient veno-occlusive mechanism. VIP is therefore not an effective monotherapy for ED, but the rationale exists for combining VIP with a substance that has a complementary action, i.e. one known to exert an affect on the arterial in-flow.

Phentolamine mesylate is a competitive nonselective α1- and α2-adrenoceptor blocker of relatively short duration of action. After i.v. injection its onset of action is rapid, the hypotensive response peaking within 5 min and lasting only 15–30 min. In the dog model, ICI resulted in a 50–100% increase in arterial blood flow without showing any impact on the veno-occlusive mechanism [17], and in humans ICI with phentolamine 5 mg only resulted in penile tumescence but not rigidity [18]. Phentolamine is therefore not suitable as monotherapy.

Combining VIP and phentolamine

Invicorp was developed in Denmark by the inventors Fahrenkrug, Ottesen and Gerstenberg, all of whom were clinicians active in this field. It was initially evaluated clinically by Gerstenberg and Metz, working in collaboration at two separate centres, and developed further by Senetek Plc (California, USA).

A logical step in the search for an effective and safe treatment for ED was to combine VIP, which has a potent effect on the veno-occlusive mechanism, but little effect on arterial inflow [12], with an agent that had the complementary properties. Phentolamine was a good candidate in that: (i) it is a licensed drug with a long history of use with an excellent safety record even at high i.v. doses; (ii) its off-label use in combination with papaverine was well documented for treating ED, where it was found to reduce the requirement for high doses of papaverine and reduce the adverse reactions associated with the latter; (iii) it provided the missing pharmacodynamic property (compared to VIP alone) required for penile erection, i.e. its action on smooth muscle, increasing arterial inflow.

The first reported use of the combination of VIP with phentolamine was in 1989, although the authors used only 2 or 4 µg of VIP with 2 mg of phentolamine, and found the combination to be ineffective [19]. Phentolamine, in doses of 0.5–3 mg, had been established as an effective agent in combination with papaverine [20]. The work using higher doses of VIP in combination with 1 or 2 mg of phentolamine led to the development of Invicorp [21]. This early long-term study included some dose ranging and showed that 0.5 mg phentolamine combined with VIP was insufficiently effective for most patients with nonpsychogenic ED, but that 1.0 mg appeared to give a generally more satisfactory response, with 2.0 mg being generally effective in those cases in which 1.0 mg was ineffective. The results of further dose-finding studies led to the conclusion that the combination of VIP and phentolamine is more effective than the individual components, and the higher-dose combinations are more effective. This observation was confirmed by the subsequent clinical studies of Invicorp, where the higher dose has been shown to be required by more seriously impaired patients with ED [21–26].

The dose-response observation was endorsed by an in vitro study that examined the response of stimulated excised human and rabbit corpus cavernosal smooth muscle to increasing doses of both VIP and phentolamine [27]. VIP caused dose-dependent relaxation in both rabbit and human cavernosal tissue strips. Furthermore, α-adrenergic blockade with phentolamine potentiated this VIP-induced relaxation in a dose-dependent manner, showing a synergistic effect between the compounds in the relaxatory response. The in vitro study, together with the dose-ranging studies, endorse the benefits of combining VIP and phentolamine in the treatment of moderate to severe ED. The response to VIP per se was minimal at the doses selected for the combined therapy, and variable at higher doses. The response to phentolamine alone was minimal in all studies regardless of dose. Therefore, the combination of VIP and phentolamine for treating nonpsychogenic ED is based on valid therapeutic principles, as required by the Committee for Proprietary Medicinal Products Note for Guidance on combination products [28]. Each component has been shown to contribute to the effect, and the level of efficacy of the combination has been shown to be greater than that achievable by either of the components individually.


Invicorp is approved in Denmark, where it has been marketed by Ardana Bioscience (London, UK) since December 2006, and it has been prescribed on a named-patient basis in the UK since mid-1995. Regulatory filings are underway in other European countries to seek pan-European approval for Invicorp under the Mutual Recognition Process. Additionally, Invicorp has been approved in New Zealand, where it has been marketed by Douglas Pharmaceuticals (New Zealand) since June 2004. Safety concerns raised by the USA Food and Drug Administration in 1999 in relation to carcinogenicity observed in animal models with a competitor’s phentolamine mesylate product (Vasomax; Zonagen Inc/Schering-Plough Corp.) resulted in a clinical hold being placed on Invicorp [29]. The clinical hold has since been lifted following the outcome of a long-term rodent study of Invicorp; the initial carcinogenicity observed in animal models was deemed to have no relevance as an indicator of carcinogenic risk in humans. Invicorp has been licensed to Plethora Solutions Plc (London, UK) for marketing within the USA, and they are working towards marketing Invicorp in the USA by the end of 2009.



The initial prescribing dose is ‘Invicorp 1’ (VIP 25 µg and phentolamine 1 mg) which can be increased to ‘Invicorp 2’ (VIP 25 µg and phentolamine 2 mg) if the effect is insufficient. Invicorp is marketed either in ampoules or in a single-use pre-filled autoinjector device (Reliaject®, Senetek Plc/Ranbaxy Pharmaceuticals Inc., USA).

Unlike other ICIs for ED, which result in full rigidity regardless of sexual stimulation, Invicorp is an erection-facilitating agent and ICI results in tumescence or semirigidity, with most patients only gaining full rigidity following visual or tactile stimulation [21]. This has resulted in reports from patients that the erection achieved with Invicorp is much more like the normal coital cycle than the action of papaverine or papaverine and phentolamine [21].

Injectable therapies for ED typically have a significant advantage over oral therapies in their rapid onset of action. The time from injection to onset of tumescence for Invicorp has been reported to be 0–5 min in 41% of patients and 5–10 min in 27% of patients [25]. Reports of the duration of erection depend on the starting point of measurement and this has varied (i.e. from tumescence or full rigidity), but is typically within 30–240 min, although this might vary depending on the aetiology of the ED [21,23]. Unlike the action of papaverine (with or without phentolamine), which results in full rigidity until the action of the drug subsides (despite ejaculation), the erection resulting from Invicorp subsides in a more natural manner after ejaculation, but with the potential for a new erection after further sexual stimulation [21].

Achievement of grade 3 erections

Several clinical studies have been conducted in Europe, and the published data from two large placebo-controlled phase III trials are summarized in Table 1[23,25]. Both trials had identical entry criteria (1-year history of predominantly nonpsychogenic ED based on medical history) and 84% of patients (in both trials) responded with a grade 3 erection (on a 0–3 scale, where grade 3 is an erection suitable for intercourse), to either Invicorp 1 or 2 during screening. This is similar to the 80% response reported by McMahon [26] in a smaller pilot study, who also noted a complete response in those with neurogenic and psychogenic causes for their ED, 78% in arteriogenic and 33% in venous leakage causes. Only patients failing to respond to Invicorp 1 in the screening/dose-titration phase were tested with Invicorp 2, hence, although the success rate of Invicorp 2, at ≈47% in both trials, appears to be lower than with Invicorp 1 per se (≈65% in both trials) it represents success in a group of patients who are harder to treat. The overall success rate of Invicorp in achieving grade 3 erections is therefore similar to published rates for other intracavernosal therapies [30].

Table 1.  The efficacy of Invicorp in patients with a history of predominantly nonpsychogenic ED; only patients failing to respond to a test dose of Invicorp 1 (25 µg VIP + 1 mg phentolamine) in the clinic and at home went on to receive the test dose of Invicorp 2 (VIP 25 µg + phentolamine 2 mg) in the screening phase. Patients who did not respond to either dose of Invicorp in the screening phase did not proceed to the placebo-controlled phase
Invicorp 1Invicorp 2*TotalInvicorp 1Invicorp 2*Total
  • *

    Four and six subjects tested positive to Invicorp 1 but went on to test Invicorp 2 in error in [25] and [23], respectively,

 N grade 3 erections/n patients (%) 204/304 (67) 55/117 (47) 255 (84)155/234 (65)52/108 (48)197 (84)
 No. patients 188 50 238 9114105
 Grade 3 erections/injection (%)
  Active1417/1886 (75)257/386 (67)1674/2272 (74)655/877 (75)92/140(66)747/1017 (74)
  Placebo  45/373 (11)  8/78 (10)  53/451 (12) 21/179 (12) 5/28 (18) 26/207 (13)
 P, active vs placebo  <0.001 <0.001  <0.001 <0.001<0.001 <0.001

Importantly, treatment success is maintained when compared with placebo over a 6- or 12-month period, with 74% of injections resulting in grade 3 erections (of a total of 3285 injections in both trials combined), with no evidence of tachyphylaxis [23,25].

Invicorp also appears to be particularly successful in patients who have failed to respond to other ICIs. A study designed to evaluate Invicorp in patients with ED resistant to other intracavernosal agents (including alprostadil and papaverine-phentolamine) reported an overall response rate of 67% (47 men) [22]. This was further supported by results from a larger study where 71 (73%) patients who withdrew from previous therapies due to poor efficacy responded to Invicorp [25]. Also, the lack of any reduced effect in older patients (>60 years) in two trials suggest that this patient group, who might have more advanced organic impairment, are equally likely to benefit from Invicorp [23,25]. This finding is supported by the reports of patients receiving Invicorp on a ‘compassionate use’ basis, with an 85% success rate in a group of 410 patients treated in the UK over a 10-year period [24], and 179 patients treated in Denmark for up to 5 years [31]. In the UK group, many patients had a high degree of comorbidity (28% hypertension, 26% coronary heart disease and 26% diabetes being the most prevalent) including 49 aged >75 years, and 89% of prescriptions were for the higher dose, Invicorp 2.

Patient-reported outcomes

In two placebo-controlled trials, overall satisfaction with the drug and the auto-injector was assessed by the patients using a follow-up questionnaire [23,25]. A similar questionnaire was also completed by patients and their partners on their quality of life. Overall, ≥85% of patients were satisfied or very satisfied with the drug and ≥92% with the auto-injector. In terms of improvements in quality of life, ≥81% of patients and ≥76% of their partners stated that their lives had been improved or greatly improved by the treatment.

In a trial comparing alprostadil and Invicorp, 67 patients received four doses each of alprostadil (presented as powder for injection), Invicorp in ampoules and Invicorp in auto-injectors, after dose titration. When asked to place the treatments in order of preference, a significantly higher proportion chose Invicorp as their first choice (P < 0.001) when comparing either Invicorp in ampoules or auto-injectors with alprostadil (Table 2) [32].

Table 2.  The order of treatment preference in 67 patients receiving four doses each of the three treatments shown (modified from [32])
Percentage1st choice2nd choice3rd choice
  • *

    P < 0.001 vs alprostadil;

  • †to minimize bias, the Invicorp in auto-injectors was always used after completing the other two treatments.

Alprostadil 82764
Invicorp in ampoules19*6120
Invicorp in auto-injector73*1215

Safety and adverse events

Not surprisingly, given the vasoactive properties of the components, facial flushing is the most common adverse event after using Invicorp and (following direct questioning) is typically experienced after 33–50% of injections [23,25], with no significant difference between Invicorp 1 and 2, but is rarely stated as a reason for discontinuing treatment. Other systemic side-effects are tachycardia/palpitations, headache and dizziness, all reported in ≤2.2% of injections [23,25]. When administered in the clinic, there were no changes in blood pressure or pulse rate after the injections [21].

ICI with alprostadil produces painful erections in up to 30% of cases [5]. More recent studies of modern formulations have found lower incidences, although a review of 20 000 patients over 15 years reported an overall incidence of 24%[33]. By contrast, penile pain after injection with Invicorp is negligible. There was no report of pain after Invicorp injection (using auto-injectors) in one 6-month study including 236 men [23], and with only 0.5% of injections in a 12-month study in which 2061 injections were used [25], despite ‘pain’ being one of the options available to tick in a list of possible side-effects in both trials. In a 187-patient trial in which Invicorp was compared with alprostadil, the proportion of injections that were associated with pain was significantly higher for alprostadil (28 per 100) than for Invicorp (three per 100; P < 0.001) [32]. Other local adverse effects reported following Invicorp use are bruising, bleeding at the injection site and urethral bleeding, possibly related to injection technique, and all typically at an incidence of <8% of injections, which are similar to rates reported for placebo injections [22,23,25].

It is well established that ICI can cause cavernosal fibrosis, particularly in the case of papaverine. In a meta-analysis of previous reports, including 15 retrospective studies, there were fibrotic changes in 5.7% and 12.4% of patients after papaverine, and a mixture of papaverine/phentolamine, respectively [30]. Fibrosis has not been reported with Invicorp, even after long-term use [24,31], and it also appears that there is no progression of pre-existing Peyronie’s plaques during or after Invicorp therapy [21].

The incidence of priapism after intracavernosal therapy has been variously reported, possibly being influenced by the dosage used, the aetiology in the patient population reported, and the criteria adopted for the definition of priapism by different authors. Incidences for alprostadil have varied between 0.07%[34] and 1%[35], with papaverine and phentolamine combination (often referred to as ‘bimix’) carrying a relatively high risk of priapism (>6 h) of 2–>10% depending on the dose used [30]. The only reports of priapism in published trials using Invicorp were three occurring in 5044 injections in two large studies [23,25], equivalent to an incidence of 0.06%. There was no report of priapism occurring in patients who have been prescribed Invicorp on a compassionate-use basis in the UK for >10 years [24]. The risk of priapism occurring with Invicorp is therefore exceptionally low.


Invicorp is a highly safe and effective treatment for ED and unlike many other ED therapies, has no known contraindications. Invicorp treatment has produced excellent results in a wide range of patients, in many of whom other therapies have failed, and it appears to be particularly suited to patients with moderate to severe ED. Other significant advantages include a rapid onset of erection after stimulation, typically within 2–5 min, a natural termination of the erection after ejaculation and a favourable safety profile. While PDE-5 inhibitors will undoubtedly remain the first choice for first-line treatment for ED, Invicorp offers an effective and safe alternative for the estimated 5.9 million men in the USA alone for whom oral ED drugs are not a viable treatment option.


Michael G. Wyllie is a Director of Plethora Solutions and W. Wallace Dinsmore is a Consultant to Plethora Solutions.