Introduction. H Porst

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1 International Journal of Impotence Research (1997) 9, 187±192 ß 1997 Stockton Press All rights reserved /97 $12.00 (medicated urethral system for erection) vs intracavernous AlprostadilÐa comparative study in 103 patients with erectile dysfunction Urological Of ce, Neuer Jungfernstieg 6a, Hamburg, Germany A comparative study in 103 unselected patients with erectile dysfunction between MUSE TM up to 1000 mg and intracavernous Alprostadil (Prostavasin TM )upto20mg provided total response-rates of 43% (MUSE TM ) vs 70% (Prostavasin TM ). Complete rigid erections were reached in 10% (MUSE TM ) vs 48% (Prostavasin TM ). The average end-diastolic ow values in the deep penile arteries ranged between 9.2±9.4 cm/s after MUSE TM and 4.5±4.8 cm/s after i.c. Alprostadil con rming the investigator's assessment, that in the vast majority of patients MUSE TM were not able to induce a complete cavernous smooth muscle relaxation. In terms of side effects the reported penile pain/burning-rate after MUSE TM was 31.4% compared to 10.6% after i.c. Alprostadil. In addition after MUSE TM clinically relevant systemic side-effects like dizziness, sweating and hypotension occurred in 5.8% with syncope in 1%. No circulatory side-effects were encountered after i.c. Alprostadil. Urethral bleeding after MUSE TM -application was observed in 4.8%. Due to the superior ef cacy and lower side-effects self-injection therapy with Alprostadil remains the `Gold Standard' in the management of male impotence. MUSE TM should be reserved for a subset of patients suffering from erectile dysfunction. Keywords: erectile dysfunction; Alprostadil; Prostaglandin E 1 ; transurethral therapy; MUSE TM ; self-injection therapy Introduction Alprostadil was proposed for intracavernous injection-therapy by Adaikan and Ishii, 1986 in Prague at the Second World Meeting on Impotence. 1,2 The publications of its usefulness and safety in larger patient groups paved the way for a world-wide acceptance of Alprostadil in self-injection therapy. 3,4 The high ef cacy and low side-effect-rates with priapisms < 1% and brotic alterations about 1% con rmed in comprehensive retrospective literature reviews prompted the Clinical Guidelines Panel on Erectile Dysfunction of the American Urological Association to the statement that Alprostadil (PGE 1 ) monotherapy should be preferred to other vasoactive drugs in self-injection therapy. 5,6 The convincing ef cacy of Alprostadil with response-rates (complete rigid erections) of > 70% in large series is attributed to several pharmacological properties of the drug: stimulation of the Correspondence: Prof. Received 1 August 1997; revised/accepted 22 September 1997 adenylate cyclase with intracellular accumulation of camp and subsequent intracellular calcium decrease, direct stimulation of the maxi K (potassium)-channels resulting in hyperpolarization, inhibition of the noradrenaline release via presynaptic EP-receptors at the alpha 1 adrenoceptors, resulting in a decrease of sympathetic (adrenergic) tone, and suppression of Angiotensin II secretion. 7±10 Each of these different pharmacological effects contributes to cavernous smooth muscle relaxation. Irrespective of the administered vasoactive drug, all published series with self-injection therapy of cavernous bodies reveal relatively high drop out rates up to 40±50% in long-term follow up. 5 This disadvantage of self-injection therapy is at least partly due to the necessity of needle-application as many patients exhibit needle-phobia. Padma- Nathan et al, 1994 for the rst time introduced transurethral application of Alprostadil by means of MUSE TM (Medicated Urethral System for Erection). 11 Due to the uncomplicated handling with a ready for use device and the needleless application MUSE TM enjoyed great popularity in a very short time and was registered in the USA in December Presently only one comprehensive publication on

2 188 this subject is available with a follow-up of three months. 12 According to this publication, the investigated patients developed erections, which were considered suf cient for sexual intercourse by several investigators in 65.9% (996 out of 1511) after transurethral Alprostadil up to 1000 mg. With the of cial approval followed by a tremendous increase of its use in erectile dysfunction critical statements on the promised ef cacy of MUSE TM could be heard which prompted us to compare ef cacy and safety of transurethral (MUSE TM ) vs intracavernously injected Alprostadil in the diagnostic evaluation of male impotence. Materials and methods Table 1 Intracavernous vs transurethral Alprostadil (MUSE TM ) One hundred and three consecutive patients (51.7 y mean) with chronic erectile dysfunction ( > 6 months) underwent a complete diagnostic evaluation with patient's history, physical examination including penile palpation, determination of serum hormone-, (testosterone, prolactine) and glucose levels and pharmacotesting of cavernous bodies. In all patients an intracavernous pharmacotesting with Alprostadil was performed up to dosages of 20 mg, in few cases up to 40 mg, respectively, and the results were compared with the outcome of transurethral application of Alprostadil with MUSE TM up to the highest dosage of 1000 mg. All investigations, including the drug administrations, were performed by the author himself. The start doses were 500 mg MUSE TM or 10 mg PGE 1 i.c., respectively, with a wash out interval of at least 48 h. In responders the dosages were lowered to 250 mg MUSE TM or 5 mg PGE 1, and in non-responders increased to 1000 mg MUSE TM or 20 m PGE 1, respectively. Both investigations were combined with a duplex-sonography of the penile arteries with determination of the systolic peak ow velocities as well as the enddiastolic ow in the deep penile arteries. The degree of erection was assessed according to an erection score of 1±5, as it was suggested in the MUSE TM studies. 12 Patients with an erection score 5 (full rigid erection) and 4 (full tumescence, partial rigidity) were considered as responders. The start of the trial either with intracavernous or with transurethral Alprostadil (MUSE TM ) was by chance. After each investigation the patients were observed for at least 60 min in the of ce with blood pressure monitoring in a sitting position and the registration of possible adverse events. At the end of the study each patient was asked upon his estimation which drug was more effective and/or better-tolerated and which drug he would prefer for home use. All patients were informed on the objective of the trial that is to nd out the best tolerable and most effective pharmacological treatment for the individual patient and all involved patients agreed to participate in the trial. Results Ef cacy (Table 1 and 2) Investigator's assessment: Complete rigid erection (ED-score 5) was obtained in 48% (49 out of 103) after i.c. Alprostadil and in 10% (10 out of 103) after MUSE TM. Full tumescence with partial rigidity (ED-Score 4) occurred in further 22% after i.c. and in 33% (34 out of 103) after transurethral Alprostadil. These numbers indicate a total response rate of 70% (72 out of 103) after i.c. Alprostadil compared to 43% (44 out of 103) after MUSE TM. The dosages required for nal assessment of the highest erection score are presented in Table 2. This table emphasizes the observations that in the majority of patients (77%) the high MUSE TM dosages of 500 mg (21%) or Table 2 Intracavernous vs transurethral Alprostadil (MUSE TM )

3 189 Table 3 Intracavernous vs Transurethral Alprostadil (MUSE TM ) 1000 mg (56%) were necessary for achievement of the highest ED-score. After i.c. Alprostadil in most patients dosages of 10 mg (28%) and 20 mg (65%) had to be applied in order to reach the highest erection quality. Table 5 Intracavernous vs Transurethral Alprostadil (MUSE TM ) Patients' subjective assessments (Table 3) After termination of the comparative trial 37.9% of the patents estimated i.c. Alprostadil superior and 15.5% inferior to MUSE TM. 46.6% of all patients indicated that they were not aware of great differences in terms of ef cacy between the both methods with the majority of these patients falling under the non-responder category. Duplex-sonography ndings (Table 4 and 5) Systolic peak ow velocities: Whereas after MUSE TM -administration the systolic peak ow velocities in the dorsal arteries were 55.6 cm/s (left side) and 53.4 cm/s (right side) were somewhat higher than after i.c. Alprostadil (49.7 and 49.0 cm/s), the ratio was conversely in terms of the deep penile arteries with a slight advantage in favour of i.c. Alprostadil (Table 4 and 5). Concerning the recorded enddiastolic ow, which represents an indirect parameter for the degree of the completeness of cavernous smooth muscle relaxation, the measured values were twice as high after MUSE TM Table 6 Intracavernous vs Transurethral Alprostadil (MUSE TM ) than after i.c. Alprostadil (Table 6). Side-Effects (Table 7) After i.c. Alprostadil 3.9% of the patients complained of severe penile pain and 6.7% of slight painful sensations during full rigid erections. On the other hand after MUSE TM -application in a total of 31% painful or burning sensations in the penis or urethra were encountered with additional 2.9% with severe testicle pain. Reddening of the varicose veins of the lower limbs with simultaneous painful sensations occurred in 2.9%. Temporary urethral bleeding after MUSE TM -application was observed in 4.8% (5 out of 103) and repeatedly occurred in four of these ve patients after further administration during the titration phase. Adverse events of general health conditions attributable to a blood pressure decay, beginning 8±15 min after application and lasting for about 10 min were observed in seven (6.8%) patients with one patient suffering from a short-term syncope. Table 4 Mean systolic peak ow velocities Discussion

4 190 Table 7 Intracavernous vs Transurethral Alprostadil (MUSE TM ) The relatively high percentage of patients with needle-phobia of any degree prompted several researchers to pursue application modalities of vasoactive drugs different from intracavernous injection-therapy. So, for example studies with intraurethral Prostaglandin E 2 -applications were published by Wolfson et al, 13 Schmidt et al, 14 Rozas et al, 15 Florante et al 16 with response-rates of up to 76%. A rst comprehensive overview on the ef cacy and safety of transurethral Alprostadil with MU- SE TM was published by Padma Nathan et al. 12 According to this paper 65.9% (996 out of 1511) of the patients had erections being considered suf cient for intercourse (erection score 4 and 5) during `in-clinic-testing'. With respect to these reported ef cacy-rates it must be realized, that in 25.4% (384 out of 1511) of all patients the erectile dysfunction was due to a condition after radical prostatectomy, therefore this patient population showed a patientselection-bias. This is in so far of importance, as patients with an underlying neurologic etiology of their erectile disturbances (damage of cavernous nerves) are more likely to respond to Alprostadil, as it was also proven in this trial with ef cacy-rates of 76.7% in the radical-prostatectomy-group compared to 65.9% in all patients. 12,17 Although only responders of the `in-clinic-titration-phase' were enrolled in a three months placebo controlled home treatment trial the success-rates after MUSE TM -application were only 50.4% (2485 out of 4933) compared to 10.4% after placebo. Similar ef cacy-rates were yielded in the Multi-Center-European MUSE TM trial. 18 In the presented cross-over study the total response-rate in unselected patients with erectile dysfunction amounted to 43% after MUSE TM compared to 70% after intracavernous Alprostadil. A subdivision of the responders (ED-score 4 and 5) showed, that only 10% (10 out of 103) of the patients had full rigid erections after MUSE TM, compared to 48% (49 out of 103) after i.c. Alprostadil. The majority of the MUSE TM -responders had incomplete erections with full tumescence and partial rigidity. These observations are re ected by the duplexsonographic blood ow measurements. Whereas the systolic peak- ow velocities of both, the dorsal arteries and the deep penile arteries revealed only insigni cant differences between MUSE TM and i.c. Alprostadil, the average enddiastolic blood ow values of the deep penile arteries ranged between 4.5 and 4.8 cm/s after i.c. Alprostadil and were twice as high after MUSE TM with 9.2±9.4 cm/s. There is general agreement in the literature, that enddiastolic- ow values above 3±5 cm/s are indicative for insuf cient cavernous smooth muscle-relaxation. 19±24 Both the assessments of the erectile response by the investigator, as well as the values of the enddiastolic blood ow in the deep penile arteries provided proof that in the majority of patients the erections, provoked by MUSE TM, are incomplete and require additionally suf cient sexual stimulation. This essential shortcoming of nonachievement of full rigidity is re ected by the fact, that only 50% of all MUSE TM -applications at home resulted in successful intercourse compared to success-rates of 87±94% after i.c. Alprostadil, which have been documented in the large prospective selfinjection trials of the companies Schwarz Pharma, Germany (Viridal TM /Edex TM ) and Pharmacia & Upjohn, USA (Caverject TM ). 12,25±28 Therefore in regard to ef cacy and reliability i.c. Alprostadil is considerably superior to MUSE TM, both in the titrationphase and in home-use. Concerning the side-effects of MUSE TM in the reported series of Padma-Nathan and the own present series the occurrence of penile/urethral pain ranked about 32% and is thus considerably higher than the reported 10±12% after intracavernous injection of Alprostadil. 5,12 A further important complication after MUSE TM -administration is the provocation of urethral lacerations with temporary bleeding out of the external urethral ori ce in 5%. 12 Although Spivack et al 29 assure that these 5% of `minor' urethral trauma resolved spontaneously without any sequelae for the urethra, it must be argued, that no appropriate investigations like urethroscopy or urethrography were conducted in the long-term follow-up of these patients with urethral trauma after MUSE TM -application. Keeping in mind the fact, that principally each minor urethral trauma may induce an urethral stricture, the statement that in long-term observations after MUSE TM -application such urethral strictures will not occur, even in cases with repeated urethral bleeding, remains an unproven speculation. Especially after the higher MUSE TM dosages of 500± 1000 mg systemic adverse events attributable to a blood pressure decay were encountered in 2±8% with syncopes in 0.4±1%. 12,29,30 Therefore it seems very important and is also recommended in the package insert of MUSE TM that the rst MUSE TM - application, especially the high dosages has to be performed in the physician's of ce with bloodpressure monitoring. The frequently encountered

5 attitude of many physicians to prescribe MUSE TM without any prior investigations on the patient's tolerability of MUSE TM to the patient in the of ce must be considered as medical mal-practice. The rate of persistent brotic penile alterations in long-term follow up (up to four years) of selfinjection therapy with Alprostadil ranged in large prospective trials between 5 and 6% and was reported 1% after MUSE TM. 28,29,31 Although this seems to be in favour of MUSE TM it has to be taken into consideration, that MUSE TM -follow up-data > 18 months are available in only 93 patients. 29 In the own series with more than 30 permanent MUSE TM -users, three patients developed brotic periurethral alterations with thickening of the ventral tunica albuginea of the cavernous bodies and with simultaneous ventral bending of the penis in two patients. Quality of life questionnaires have provided convincing proof that self-injection therapy with Alprostadil and transurethral therapy with MUSE TM have a positive impact on quality of life parameters like self esteem, emotional well-being and in uence on partnership. 28,32,33 These important positive in- uences on patients and the partnership render both methods indispensable in the therapeutic management of male impotence. The needleless administration with a very user-friendly application device prompt many patients to prefer MUSE TM to selfinjection therapy and those patients in whom MUSE TM works reliably at home are very satis ed with this new therapeutic option. On the other hand the considerably lower ef cacy of MUSE TM compared to i.c. Alprostadil exclude the majority of impotent patients from MUSE TM -therapy in whom self-injection therapy will however be effective. In addition whereas the drug-safety is nally assessed for self-injection therapy, this is not true for MUSE TM especially with regard to penile brosis and the possibility of urethral strictures. Regarding ef cacy and reliability of both methods, self-injection therapy with Alprostadil will remain the `Gold Standard' in the pharmacological treatment of erectile dysfunction, while MUSE TM will be reserved for a subset of these patients. References 1 Adaikan PG, Kottegoda SR, Ratnam SS. A possible role for prostaglandin E 1 in human penile erection. In: Abstract Book Second World Meeting on Impotence, Prague 1986; Abs Ishii N, Watanabe H, Irisawa C, Kikuchi Y. Therapeutic trial with prostaglandin E 1 for organic impotence. In: Abstract Book Second World Meeting on Impotence, Prague 1986; Abs Porst H. Comparative usefulness of prostaglandin E 1, papaverine and papaverine/phentolamine for the diagnosis of erectile dysfunction in 61 patients. Urologe A 1988; 27: 22±26. 4 Stackl W, Hasun R, Marberger M. Intracavernous injection of prostaglandin E 1 in impotent men. J Urol 1988; 140: Porst H. Review Article. The rationale for prostaglandin E 1 in erectile failure: a survey of worldwide experience. J Urol 1996; 155: 802± Montague DK et al. Clinical guidelines panel on erectile dysfunction: summary report on the treatment of organic erectile dysfunction. J Urol 1996; 156: 2007± Palmer LS et al. Characterization of cyclic AMP accumulation in cultured human corpus cavernosum smooth muscle cells. J Urol 1994; 152: 1308± Zhang P, Christ GJ, Brink PR, Ney P. PGE 1 -induced alterations in maxi-k channel activity in cultured human corporal smooth muscle cells. J Urol 1996; 155 (Suppl) 678A: Molderings GJ, van Ahlen H, GoÈthert M. Modulation of noradrenalin release in human corpus cavernosum by presynaptic prostaglandin receptors. Int J Impot Res 1992; 4: Kifor I et al. Tissue angiotensin II as a modulator of erectile function. I. angiotensin peptide content, secretion and effects in the corpus cavernosum. J Urol 1997; 157: 1920± Padma-Nathan H et al. Hemodynamic effects of intraurethral Alprostadil: The Medicated Urethral System for Erection (MUSE 1 ). J Urol 1994; 151: 345A: Padma-Nathan H et al. for the MUSE 1 Study Group. Treatment of men with erectile dysfunction with transurethral Alprostadil. New Engl J Med 1997; 336: 1±7. 13 Wolfson B et al. Intraurethral Prostaglandin E 2 cream: a possible alternative treatment for erectile dysfunction. Urology 1993; 42: 73± Schmidt AC. Prostaglandin E2 gel: an alternative treatment for erectile dysfunction. Int J Impot Res 1994; 6 (Suppl 1): A Rozas KP et al. Intraurethral prostaglandin for the treatment of postprostatectomy impotence. J Urol 1995; 153 (Suppl) 473A: Florante J, Leyson J. Comparative study between transdermal and transurethral prostaglandin E 2 in the treatment of impotence in neurologically impaired patients. J Urol 1995; 153 (Suppl) 482A: Costabile RA et al. on behalf of the VIVUS-MUSE Study Group. Ef cacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J Urol 1997; 157 (Suppl) 364: Porst H et al. and the European VIVUS-MUSE 1 Study Group. Transurethral Alprostadil for the treatment of chronic erectile dysfunction: the European experience. Int J Impot Res 1996; 8: 131; D Barrett DM, Nehra A, King BF. Hemodynamic interpretation following redosing during duplex doppler ultrasonography: is there a change in diagnosis? J Urol 1997; 157(4) (Suppl) 179: Kropman RF et al. Relation of intracorporal pressure and enddiastolic velocity during duplex-dopplersonography in the evaluation of veno-occlusive dysfunction. Int J Impot Res 1994; 6: 125± Rhee E, Osborn A, Witt M. The correlation of cavernous systolic occlusion pressure with peak velocity ow using color duplex doppler ultrasound. J Urol 1995; 153: 358± Wegner HEH et al. Evaluation of penile arteries with colorcoded duplex sonography: prevalence and possible therapeutic implications of connections between dorsal and cavernous arteries in impotent men. J Urol 1995; 156: 1469± Martins FE, Padma-Nathan H. Diffuse veno-occlusive dysfunction: the underlying hemodynamic abnormality resulting in failure to respond to intracavernous pharmacotherapy. J Urol 1996; 156: 1942± Sattar AA et al. Correlation of nocturnal penile tumescence monitoring duplex ultrasonography and infusion cavernosometry for the diagnosis of erectile dysfunction. J Urol 1996; 155: 1274± Linet OI, Ogrinc FG and Alprostadil Study Group. Ef cacy and safety of intracavernosal Alprostadil in men with erectile dysfunction. New Engl J Med 1996; 334: 873± Lea AP, Bryson HM, Balfour JA. Intracavernous Alprostadil. A 191

6 192 review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in erectile dysfunction. Drugs and Aging 1996; Jan 8(1): 56± Porst H et al. Self-injection therapy with prostaglandin E 1 : long-term results of an international multicenter study according to the GCP-Standard. Int J Impot Res 1994; 6 (Suppl 1): D Porst H et al. Final results of a prospective multicenter-study with self-injection therapy with PGE 1 after 4 years of followup. Int J Impot Res 1996; 8(3) 151: D Spivack AP et al. on behalf of the VIVUS-MUSE 1 Study Group. Long-term safety pro le of trans-urethral alprostadil for the treatment of erectile dysfunction. J Urol 1997; 157 (Suppl) 203: FDA-Documents for MUSE TM approval Linet OI, Ogrinc FG. Penile brosis during 18 months of intracavernosal therapy with Alprostadil (Caverject 1 ). Int J Impot Res 1996; 8(3): D O'Leary MP et al. for the MUSE 1 Study Group. Transurethral Alprostadil improves quality of life for patients and partners. Int J Impot Res 1996; 8(3): A Wilke RJ et al. Quality of life effects of Alprostadil therapy for erectile dysfunction in the U.S. and Europe. Int J Impot Res 1996; 8(3): 113; A58.

Review of intraurethral suppositories and iontophoresis therapy for erectile dysfunction

(2000) 12, Suppl 4, S86±S90 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Review of intraurethral suppositories and iontophoresis therapy for erectile dysfunction