Rationale for Combination Therapy of Intraurethral Prostaglandin E1 and Sildenaﬁl in the Salvage of Erectile Dysfunction Patients Desiring Noninvasive Therapy

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Rationale for combination therapy of intraurethral prostaglandin E1 and sildenaﬁl in the salvage of erectile dysfunction patients desiring noninvasive therapy

A Nehra1*, ML Blute1, DM Barrett2 and RB Moreland3{

1Department of Urology, Mayo Clinic and Foundation, Rochester, Minnesota, USA; 2Department of Urology, Lahey Clinic, Burlington, Massachusetts, USA; and 3Department of Urology, Boston University Medical School, Boston, Massachusetts, USA

Corpus cavernosum smooth muscle relaxation and hence penile erection are regulated in part by increases in smooth muscle synthesis of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The object of this study was to determine 30-month follow-up results in motivated patients desiring noninvasive medical therapy using sildenafil citrate (Viagra) in combination with intraurethral prostaglandin E1 (PGE1) (Medicated Urethral System for Erection [MUSE]). Twenty-eight patients (mean Æ s.d. age, 59 Æ 7.3 y; 17 who had undergone radical prostatectomy and 11 who had a diagnosis of organic erectile dysfunction) were included in this study. Detailed history taking and physical examinations were performed and vascular risk factors noted. In these patients, treatment with either 100 mg of sildenafil citrate and=or 1000 mg of MUSE had failed. None of these patients desired intracavernosal injection. Duplex Doppler ultrasonography after redosing was carried out on all patients. Dynamic infusion corpus cavernosography=cavernosometry was obtained in 17 of 28 patients, and combination therapy was initiated using 100 mg of sildenafil citrate orally 60 min before intercourse and 500 mg of MUSE intraurethrally immediately before intercourse. Independently, either 100 mg of sildenafil citrate or 1000 mg of MUSE was not efficacious in inducing an erection sufficient for vaginal penetration in any of the 28 patients. After initiating a combination therapy, at 30 months, all 28 patients were reporting erections sufficient for vaginal penetration, with 3.6 intercourse episodes per month. None of the patients crossed over to intracavernosal therapy or penile prosthesis. During therapy, eight of 28 patients reduced the dose of sildenafil citrate to 50 mg. Combination therapy with MUSE and sildenafil may be more efficacious in the salvage of patients who desire noninvasive therapy but in whom single-treatment modalities fail. Although both cAMP- and cGMP-mediated vasodilation can lead to penile erection, combining therapies that incorporate both pathways may succeed when single therapies fail. International Journal of Impotence Research (2002) 14, Suppl 1, S38–S42. DOI: 10.1038= sj=ijir=3900795

Keywords: radical prostatectomy; MUSE; sildenaﬁl; prostaglandin E1; minimally invasive therapy; cyclic guanosine monophosphate; cyclic adenosine monophosphate

Introduction may not compare to the clinical trials conducted both with healthy volunteers and subsequently with patients with minimal and moderate erectile dys- The advent of oral sildenafil citrate (Viagra) has function.1–5 A recent report from a general urology heralded a new wave of enthusiasm by patients practice notes some of these discrepancies.6 Further, seeking noninvasive treatment for male erectile differences in objective assessment of tumescence dysfunction. Unfortunately, the efficacy and out- and frequency of penetration, as assessed by the comes determined in the general urology practice International Index of Erectile Function (IIEF), have been highlighted in two recent cohorts: patients with spinal cord injury3,4 and diabetic patients.5 In *Correspondence: A Nehra, Department of Urology, Mayo the spinal cord injury group, although a significant Clinic and Foundation, 200 First St SW, Rochester, MN improvement was documented in sexual satisfac- 55905, USA. E-mail: [email protected] tion, there was no significant difference in penile {Dr Moreland is currently with Neuroscience Department rigidity between the placebo- and sildenafil-treated 4ND, GPRD, Building AP9, Abbott Laboratories, 100 Abbott patients as documented by the IIEF.3,4 In the Park Rd, Abbott Park, IL 60064-6118, USA. diabetic cohort, there was a significant difference MUSE-sildenafil combination therapy A Nehra et al S39 in both parameters (tumescence and penetration); intracavernosal therapy were included in this study. however, a large number of patients were not A detailed history taking and physical examination successful in intercourse attempts.4 Likewise, the were performed and vascular risk factors noted initial success of the Medical Urethral System for (Table 1). Fifteen of 17 prostatectomy patients had Erection (MUSE) (intraurethral prostaglandin E1 undergone bilateral nerve-sparing radical retropub- 7,8 [PGE1]) has been difficult to duplicate in the lic prostatectomies (RRPs), whereas the remaining office setting.9 – 11 It is also important to note the two prostatectomy patients had undergone unilat- different mechanisms by which sildenafil and PGE1 eral nerve-sparing procedures. The RRPs had been relax the corpus cavernosum trabecular smooth performed less than 5 months previously in all muscle, albeit by different pathways, and hence patients at the time of initiation of therapy. Patients facilitate erection.1 were instructed to self-titrate themselves to a dose of Corpus cavernosum smooth muscle relaxation either 100 mg of sildenafil citrate and=or 1000 mgof and hence penile erection are regulated in part by MUSE intraurethrally before consideration of com- increases in smooth muscle synthesis of the second bination therapy. Duplex Doppler ultrasonography messengers cyclic adenosine monophosphate with redosing was performed in all of the patients (cAMP) and cyclic guanosine monophosphate before combination therapy. In all of the radical (cGMP).1 There are indirect- and direct-acting prostatectomy patients, dynamic infusion corpus smooth muscle-relaxing agents. Phosphodiesterase cavernosometry=cavernosography was performed (PDE) inhibitors such as sildenafil act indirectly and after redosing.10 None of these patients desired require sexual stimulation and endogenous nitric intracavernosal injection, and combination therapy oxide production for efficacy, activating the cGMP was initiated using 100 mg of sildenafil citrate orally pathway. In contrast, agents such as PGE1 act 60 min before intercourse and 500 mg of MUSE directly on the trabecular smooth muscle, binding intraurethrally immediately before intercourse. to specific EP receptors and increasing cAMP synthesis.1,9 As such, the direct-acting agents do not require sexual stimulation for efficacy. Results In this report, we examine the effectiveness of MUSE-sildenafil combination therapy in 28 motivated patients in whom each individual therapy had Vascular risk factors have been associated with and failed but who did not wish to have more invasive can be predictive of erectile dysfunction.1 Of the therapies such as intracavernosal injection. radical prostatectomy patients in our study, all had only one vascular risk factor. None of these patients were obese (body mass index [BMI] > 30), had sleep Methods apnea, or reported smoking. Four reported hypertension, with one using diet to control the condition. Three reported type 2 diabetes mellitus. With the Twenty-eight patients (17 who had undergone organic erectile dysfunction patients, none of the radical prostatectomy and 11 who had a diagnosis patients were obese or reported sleep apnea. Of of organic erectile dysfunction) with a mean Æ s.d. the seven that reported hypertension, two also age of 59 y (range, 51 – 66 y) who did not desire complained of diabetes. Aside from those two

Table 1 Preoperative vascular risk factors for the study populationa

Radical retropubic prostatectomy Organic erectile dysfunction Risk factors patients (n ¼ 17) patients (n ¼ 11)

Obesity (body mass index > 30) 0 0 Sleep apnea 0 0 Hypertension 4 7c Diet-controlled hypertension 1 0 Angiotensin-converting enzyme inhibitors 3 6 Angiotensin-converting enzyme inhibitor a-blockers 0 1 Type 2 diabetes mellitus 3 2 Medications 2 2 Cigarette smoking 0b 2d aThe mean age of study participants was 56 y (range, 51 – 66 y) in the radical retropubic prostatectomy group and 59 y (range, 46 – 68 y) in the organic erectile dysfunction group. Of the patients in the radical retropubic prostatectomy group, two underwent unilateral nerve- sparing procedures and 15 underwent bilateral nerve-sparing procedures. bFive patients had a smoking history of 10 pack-years but stopped more than 15 y ago. cTwo patients had hypertension and diabetes. dCurrently, n ¼ 2; 0.5 packs per day for the last 20 y; six of nine patients stopped smoking more than 12 y ago.

International Journal of Impotence Research MUSE-sildenafil combination therapy A Nehra et al S40 patients, all had one vascular risk factor. Blood work Discussion revealed that all hormonal values in both sets of patients were within normal limits. On examination with duplex Doppler ultrasonography following In this study, highly motivated men who did not intracavernous injection of PGE1 (10 mg) for diag- have satisfactory results with either sildenafil nosis, of the 11 patients with potential organic (Viagra) or MUSE (intraurethral PGE1) were able to erectile dysfunction, three had defined veno-occlu- achieve erections sufficient for sexual intercourse sive dysfunction and two had cavernosal artery using a combination of the two therapies. This insufficiency, all despite redosing. All of the RRP cohort of patients was composed of both men with patients had normal cavernosal inflows as assessed organic erectile dysfunction (11=28) and preopera- by duplex Doppler ultrasonography. The RRP tively potent men who had undergone radical patients were further subjected to dynamic infusion prostatectomy (17=28). Initial dosing was carried corpus cavernosometry= out in the clinical setting to assess any adverse cavernosography. All 17 patients were diagnosed as events. None were observed. having veno-occlusive dysfunction with diffuse What is the pharmacologic rationale for the leakage present at crural (2 þ ), dorsal (2 þ ), caver- failure of one drug that when used in combination nosal (1 þ ), and spongiosal (1 þ ) sites. with another results in penile erection rigid enough This entire cohort of patients was typified by a for penetration? This patient cohort was composed high degree of motivation to treat their erectile of highly motivated individuals who desired non- dysfunction and substantial anxiety regarding invasive or minimally invasive therapy. For this intracavernous injection therapy or surgery and group, despite its efficacy, intracavernosal injection the ability to regain sexual function. In all was not an option. This group was composed of 62% patients, 100 mg of sildenafil citrate or 1000 mg of nerve-sparing RRP patients and 38% with of MUSE independently, although inducing some vasculogenic erectile dysfunction of varying origins. penile tumescence, was not efficacious in facil- In all patients, a trial of oral 100 mg of sildenafil itating an erection sufficient for vaginal penetra- citrate failed to result in rigid penile erection, tion. This corroborates the poor response of although most patients reported some tumescence. radical prostatectomy patients treated with silde- In 60% of patients, MUSE, either at the 500- or 1000- nafil recently reported,6 but disagrees with the mg dose, also failed to result in rigid penile erection. success other clinicians have found with bilat- Why should a combination of drugs be efficacious? eral nerve-sparing radical prostatectomy patients It is our hypothesis that sildenafil, by inhibiting who are undergoing sildenafil therapy.12 Further, trabecular smooth muscle PDE-5 and thus increas- these observations are consistent with the mixed ing intracellular concentrations of cGMP and MUSE responses noted with patients using (PGE1) and cAMP synthesis via activation of EP2 MUSE.11,13,14 and=or EP4 receptors on the smooth muscle cells, After the first regimen of treatment failed, these results in two different pathways that converge on highly anxious, self-motivated patients began myosin dephosphorylation and smooth muscle combination therapy. Initial dosing was performed relaxation (Figure 1). Since both pathways operate in the office setting to closely monitor any adverse in the normal physiology of erection (cGMP via effects. No positional hypotension, priapism, or nitric oxide stimulation of guanylate cyclase and other cardiovascular episodes were noted in any cAMP via vasoactive intestinal polypeptide, calci- of the 28 patients. Further, there was no evidence tonin gene-related peptide, and endogenous PGE of abnormal electrocardiogram results, angina, or stimulation of adenylate cyclase), enhancing intra- peripheral vascular complications. Combination cellular cyclic nucleotide concentrations from both therapy, including a lower dose of MUSE pathways would probably be beneficial. Combina- (500 mg) and 100 mg of sildenafil citrate, was most tion pharmacotherapy has been used in the treat- effective in inducing an erection sufficient for ment of erectile dysfunction in an experimental vaginal penetration. At 30 months, all patients are fashion for 25 y, using combinations of cAMP reporting reproducible results and continue to use synthesis augmentors (PGE), smooth muscle relax- the combination therapy, with 3.6 intercourse ants and PDE inhibitors (papaverine), and a- episodes per month. None have crossed over to blockers (phentolamine) injected intracavernosally. intracavernosal therapy or penile prosthesis. Dur- Although in this case the endogenous nitric oxide ing therapy, eight of the 28 patients had reduced pathway might be expected to contribute to cGMP their dose of sildenafil citrate to 50 mg. The levels, this is the first report in which pharma- General Assessment Question score (‘Has this cotherapeutic augmentation of both cAMP and medication improved your erections?’)wentfrom cGMP pathways has been attempted in a minimally 0% to 100% in all 28 patients. MUSE-sildenafil invasive or noninvasive therapy.15 combinations were well tolerated in this cohort What is the evidence for cAMP=cGMP crosstalk of patients with excellent patient and partner or synergy? Processes that increase cAMP may satisfaction. enhance cGMP levels as well. Kim et al16 have

International Journal of Impotence Research MUSE-sildenaﬁl combination therapy A Nehra et al S41

Figure 1 Working hypotheses. Nitric oxide (NO) is generated from neural and endothelial sources and diffuses into corpus cavernosum smooth muscle and binds to soluble guanylate cyclase (GC). Guanosine triphosphate (GTP) is converted to cyclic guanosine monophosphate (cGMP), which ultimately results in smooth muscle relaxation. Phosphodiesterase 5 (PDE-5) converts cGMP to GMP, terminating signal transduction. Prostaglandin E1 (PGE1) binds to EP2=EP4 receptors, stimulating adenylate cyclase (AC) and converting adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). cAMP can also lead to smooth muscle relaxation and inhibit PDE-5. observed that cAMP can inhibit PDE-5 in vitro and References treatments that increase cAMP (PGE1, forskolin) enhance cGMP synthesis in human corpus cavernosum smooth muscle cells. Repeated intracavernous 1 Nehra A, Barrett DM, Moreland RB. Pharmacotherapeutic advances in the treatment of erectile dysfunction. Mayo Clin PGE1 injections have been reported to up-regulate Proc 1999; 74: 709 – 722. nitric oxide synthase expression in a rat animal 2 Goldstein I et al for the Sildenafil Study Group. Oral sildenafil model.17 Increased cAMP may also dampen the a- in the treatment of erectile dysfunction. New Engl J Med 1998; adrenergic response in corpora cavernosa by down- 338: 1397 – 1404. 3 Derry FA et al.Efficacy and safety of oral sildenafil (Viagra) in regulating expression of contractile a-adrenergic men with erectile dysfunction caused by spinal cord injury. 18 receptors in the penis. Finally, because this was Neurology 1998; 51: 1629 – 1633. a group of anxious patients, combination therapy 4 Maytom MC et al. A two-part study of sildenafil (ViagraTM)in may be much more efficacious in counteracting the men with erectile dysfunction caused by spinal cord injury. potential increased adrenergic tone as a result of Spinal Cord 1999; 37: 110 – 116. 5 Rendell MS, Rajfer J, Wicker PA, Smith MD, and the Sildenafil circulating catecholamines. Diabetes Study Group. Sildenafil for treatment of erectile Combination therapy of MUSE and sildenafilis dysfunction in men with diabetes: a randomized controlled more effective in the salvage of patients who desire trial. JAMA 1999; 281: 421 – 426. noninvasive therapy but in whom single-treatment 6 Marks LS et al. Treatment of erectile dysfunction with sildenafil. Urology 1999; 53:19– 24. modalities fail. Although both cAMP- and 7 Hellstrom WJ et al. A double-blind, placebo-controlled cGMP-mediated vasodilation can lead to corpus evaluation of the erectile response to transurethral alprostadil. cavernosum smooth muscle relaxation and erection, Urology 1996; 48: 851 – 856. combining the different mechanistic pathways may 8 Padma-Nathan H et al. Treatment of men with erectile succeed where use of a single agent (cAMP or dysfunction with transurethral alprostadil. New Engl J Med 1997; 336:1– 7. cGMP) fails. This may be in part due to high doses of 9 Moreland RB et al. Oxygen-dependent prostanoid synthesis PGE1-inducing contraction in the corpus caverno- activates functional PGE receptors on human corpus cavernosum via thromboxane receptors18 or inability of a sum smooth muscle cells. Am J Physiol 2001; 281:H552– H558. single agent to overcome the norepinephrine-in- 10 Hatzichristou DG et al. In vivo assessment of trabecular smooth muscle tone, its application in pharmacocavernoso- duced a-adrenergic mechanism in the penis in metry and analysis of intracavernosal pressure determinants. anxious patients. Furthermore, although neither J Urol 1995; 153: 1126 – 1131. MUSE nor sildenafil alone was sufficient to induce 11 Porst H. Transurethral Alprostadil with MUSETM (medicated erection, blockade of both the cAMP and cGMP urethral system for erection) vs intracavernous Alprostadil: a pathways may be a means of enhancing trabecular comparative study in 103 patients with erectile dysfunction. Int J Impot Res 1997; 9: 187 – 192. smooth muscle relaxation not unlike what has been 12 Zippe CD et al. Treatment of erectile dysfunction after radical reported for intracavernosal injection of single prostatectomy with sildenafil citrate (Viagra). Urology 1998; agents (for example, PGE1, papaverine) vs double- 52: 963 – 966. TM agent and triple-agent modalities. In conclusion, in 13 Werthman P, Rajfer J. MUSE therapy: preliminary clinical observations. Urology 1998; 50: 809 – 811. this cohort of 28 patients, MUSE-sildenafil combi- 14 Fulgham PF et al. Disappointing initial results with transur- nations were well tolerated with excellent patient ethral alprostadil for erectile dysfunction in a urology practice and partner satisfaction. setting. J Urol 1998; 160: 2041 – 2046.

International Journal of Impotence Research MUSE-sildenaﬁl combination therapy A Nehra et al S42 15 Nehra A, Jones WR, Hakim L, Moreland RB. Effectiveness of 18 Traish A et al. cAMP regulates mRNA expression of E1 alpha combination therapy of MUSETM and ViagraTM in the salvage 1D and alpha 2A adrenergic receptors in cultured human of erectile dysfunction patients desiring noninvasive therapy. corpus cavernosum smooth muscle cells. Int J Impot Res 2000; J Urol 1999; 161(Suppl 4): 215, abstract 815. 12(Suppl 1): S41 – S47. 16 Kim NN et al. Cross-regulation of intracellular cGMP and 19 Moreland RB, Nehra A, Goldstein I, Traish AM. The role of cAMP in cultured human corpus cavernosum smooth muscle prostaglandin E as determined by expression of functional cells. Cell Mol Biol Res Comm 2000; 4:10– 14. prostaglandin E receptors in human corpus cavernosum. J Urol 17 Escrig A, Marin R, Mas M. Repeated PGE1 treatment enhances 1999; 161(Suppl 4): 218, abstract 837. nitric oxide and erection responses to nerve stimulation in the rat penis by upregulating constitutive NOS isoforms. J Urol 1999; 162: 2205 – 2210.

Appendix Dr Montorsi: Any feeling on the difference that there may be between pain from injections and pain from Open discussion following Dr Nehra’s presentation MUSE in these patients? Dr Nehra: We’ve all had experience with patients who use penile injection therapy having classically Dr Wespes: How long does this treatment take to be increased anxiety and pain with the first few effective? months. Then they come back to you and say it’s Dr Nehra: The patients needed about three to four second nature to me. I used to feel the thing, but attempts at home with MUSE to be successful. now it’s more a perception to me than really feeling Dr Carson: How do you instruct them to take the it. medication? Dr Hatzichristou: In this specific group, were you Dr Nehra: The key is you have to have them take the dealing with radical prostatectomy patients? pill first because of the onset of action. These Dr Nehra: Those were the patients who had pain patients were really instructed very well by two of with therapy. It’s the patients you wait a little bit our nurses in the outpatient clinic. A lot of time was before treating who are not having discomfort. spent with them with respect to MUSE therapy and Dr Montorsi: I have the feeling that if you start Viagra, so the medication was very well timed. treatment right after the surgery, pain will be less. Dr Montorsi: How many of these patients reported We have been using Trimix. If you use Trimix, then pain? How long after the surgery did they start the pain rate decreases dramatically. It is more treatment? effective and cheaper. Dr Nehra: They started treatment 4 months after Dr Nehra: Pharmacologically that makes sense as surgery. I’d say about 30% to 40% had pain, but it well, because you’re using PGE1 at a significantly wasn’t enough for them to stop the therapy. lower dose.

International Journal of Impotence Research