Transurethral Alprostadil with MUSETM (Medicated

Home , Intracavernous injection

Transurethral Alprostadil with MUSETM (medicated urethral system for erection) vs intracavernous AlprostadilÐa comparative study in 103 patients with erectile dysfunction

H Porst

Urological Of®ce, Neuer Jungfernstieg 6a, 20354 Hamburg, Germany

A comparative study in 103 unselected patients with erectile dysfunction between MUSETM up to 1000 mg and intracavernous Alprostadil (ProstavasinTM)upto20mg provided total response-rates of 43% (MUSETM) vs 70% (ProstavasinTM). Complete rigid erections were reached in 10% (MUSETM) vs 48% (ProstavasinTM). The average end-diastolic ¯ow values in the deep penile arteries ranged between 9.2±9.4 cm/s after MUSETM and 4.5±4.8 cm/s after i.c. Alprostadil con®rming the investigator's assessment, that in the vast majority of patients MUSETM were not able to induce a complete cavernous smooth muscle relaxation. In terms of side effects the reported penile pain/burning-rate after MUSETM was 31.4% compared to 10.6% after i.c. Alprostadil. In addition after MUSETM 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 MUSETM-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. MUSETM should be reserved for a subset of patients suffering from erectile dysfunction.

TM Keywords: erectile dysfunction; Alprostadil; Prostaglandin E1; transurethral therapy; MUSE ; self-injection therapy

Introduction adenylate cyclase with intracellular accumulation of cAMP and subsequent intracellular calcium decrease, direct stimulation of the maxi K (potas- Alprostadil was proposed for intracavernous injec- sium)-channels resulting in hyperpolarization, in- tion-therapy by Adaikan and Ishii, 1986 in Prague at hibition of the noradrenaline release via presynaptic the Second World Meeting on Impotence.1,2 The EP-receptors at the alpha1 adrenoceptors, resulting publications of its usefulness and safety in larger in a decrease of sympathetic (adrenergic) tone, and patient groups paved the way for a world-wide suppression of Angiotensin II secretion.7±10 Each of acceptance of Alprostadil in self-injection ther- these different pharmacological effects contributes apy.3,4 The high ef®cacy and low side-effect-rates to cavernous smooth muscle relaxation. with priapisms < 1% and ®brotic alterations about Irrespective of the administered vasoactive drug, 1% con®rmed in comprehensive retrospective lit- all published series with self-injection therapy of erature reviews prompted the Clinical Guidelines cavernous bodies reveal relatively high drop out Panel on Erectile Dysfunction of the American rates up to 40±50% in long-term follow up.5 This Urological Association to the statement that Alpros- disadvantage of self-injection therapy is at least tadil (PGE1) monotherapy should be preferred to partly due to the necessity of needle-application as other vasoactive drugs in self-injection therapy.5,6 many patients exhibit needle-phobia. Padma- The convincing ef®cacy of Alprostadil with Nathan et al, 1994 for the ®rst time introduced response-rates (complete rigid erections) of > 70% transurethral application of Alprostadil by means of in large series is attributed to several pharmacolo- MUSETM (Medicated Urethral System for Erection).11 gical properties of the drug: stimulation of the Due to the uncomplicated handling with a ready for use device and the needleless application MUSETM enjoyed great popularity in a very short time and Correspondence: Prof H Porst. was registered in the USA in December 1996. Received 1 August 1997; revised/accepted 22 September 1997 Presently only one comprehensive publication on Transurethral Alprostadil with MUSETM H Porst 188 this subject is available with a follow-up of three months.12 According to this publication, the inves- tigated 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 MUSETM could be heard which prompted us to compare ef®cacy and safety of transurethral (MUSETM) vs intracavernously injected Alprostadil in the diagnostic evaluation of male impotence.

Table 1 Intracavernous vs transurethral Alprostadil (MUSETM) Materials and methods

One hundred and three consecutive patients (51.7 y mean) with chronic erectile dysfunction ( > 6 and all involved patients agreed to participate in the months) underwent a complete diagnostic evalua- trial. tion with patient's history, physical examination including penile palpation, determination of serum hormone-, (testosterone, prolactine) and glucose Results levels and pharmacotesting of cavernous bodies. In all patients an intracavernous pharmacotesting Ef®cacy (Table 1 and 2) with Alprostadil was performed up to dosages of 20 mg, in few cases up to 40 mg, respectively, and the Investigator's assessment: Complete rigid erec- results were compared with the outcome of transur- tion (ED-score 5) was obtained in 48% (49 out of ethral application of Alprostadil with MUSETM up to 103) after i.c. Alprostadil and in 10% (10 out of 103) the highest dosage of 1000 mg. All investigations, after MUSETM. Full tumescence with partial rigidity including the drug administrations, were performed (ED-Score 4) occurred in further 22% after i.c. and in by the author himself. The start doses were 500 mg 33% (34 out of 103) after transurethral Alprostadil. TM MUSE or 10 mg PGE1 i.c., respectively, with a wash These numbers indicate a total response rate of 70% out interval of at least 48 h. In responders the (72 out of 103) after i.c. Alprostadil compared to dosages were lowered to 250 mg MUSETM or 5 mg 43% (44 out of 103) after MUSETM. The dosages PGE1, and in non-responders increased to 1000 mg required for ®nal assessment of the highest erection TM MUSE or 20 m PGE1, respectively. Both investiga- score are presented in Table 2. This table empha- tions were combined with a duplex-sonography of sizes the observations that in the majority of patients the penile arteries with determination of the systolic (77%) the high MUSETMdosages of 500 mg (21%) or 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 MUSETM 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 (MUSETM) 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 Table 2 Intracavernous vs transurethral Alprostadil (MUSETM) Transurethral Alprostadil with MUSETM H Porst 189

Table 3 Intracavernous vs Transurethral Alprostadil (MUSETM) Table 5 Intracavernous vs Transurethral Alprostadil (MUSETM) 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.

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 MUSETM. 46.6% of all patients indicated that they were not aware of great differ- Table 6 Intracavernous vs Transurethral Alprostadil (MUSETM) ences in terms of ef®cacy between the both methods with the majority of these patients falling under the non-responder category. than after i.c. Alprostadil (Table 6).

Duplex-sonography ®ndings (Table 4 and 5)

Systolic peak ¯ow velocities: Whereas after Side-Effects (Table 7) MUSETM-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 After i.c. Alprostadil 3.9% of the patients com- than after i.c. Alprostadil (49.7 and 49.0 cm/s), the plained of severe penile pain and 6.7% of slight ratio was conversely in terms of the deep penile painful sensations during full rigid erections. On the arteries with a slight advantage in favour of i.c. other hand after MUSETM-application in a total of Alprostadil (Table 4 and 5). Concerning the re- 31% painful or burning sensations in the penis or corded enddiastolic ¯ow, which represents an urethra were encountered with additional 2.9% indirect parameter for the degree of the complete- with severe testicle pain. Reddening of the varicose ness of cavernous smooth muscle relaxation, the veins of the lower limbs with simultaneous painful measured values were twice as high after MUSETM sensations occurred in 2.9%. Temporary urethral bleeding after MUSETM-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 Transurethral Alprostadil with MUSETM H Porst 190 the systolic peak-¯ow velocities of both, the dorsal arteries and the deep penile arteries revealed only insigni®cant differences between MUSETM 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 MUSETM 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 Table 7 Intracavernous vs Transurethral Alprostadil (MUSETM) of the enddiastolic blood ¯ow in the deep penile arteries provided proof that in the majority of patients the erections, provoked by MUSETM, are The relatively high percentage of patients with incomplete and require additionally suf®cient sex- needle-phobia of any degree prompted several ual stimulation. This essential shortcoming of non- researchers to pursue application modalities of achievement of full rigidity is re¯ected by the fact, vasoactive drugs different from intracavernous in- that only 50% of all MUSETM-applications at home jection-therapy. So, for example studies with in- resulted in successful intercourse compared to traurethral Prostaglandin E2-applications were success-rates of 87±94% after i.c. Alprostadil, which published by Wolfson et al,13 Schmidt et al,14 Rozas have been documented in the large prospective self- et al,15 Florante et al16 with response-rates of up to injection trials of the companies Schwarz Pharma, 76%. A ®rst comprehensive overview on the ef®cacy Germany (ViridalTM/EdexTM) and Pharmacia & Up- and safety of transurethral Alprostadil with MU- john, USA (CaverjectTM).12,25±28 Therefore in regard SETM was published by Padma Nathan et al.12 to ef®cacy and reliability i.c. Alprostadil is con- According to this paper 65.9% (996 out of 1511) of siderably superior to MUSETM, both in the titration- the patients had erections being considered suf®- phase and in home-use. cient for intercourse (erection score 4 and 5) during Concerning the side-effects of MUSETM in the `in-clinic-testing'. With respect to these reported reported series of Padma-Nathan and the own ef®cacy-rates it must be realized, that in 25.4% (384 present series the occurrence of penile/urethral pain out of 1511) of all patients the erectile dysfunction ranked about 32% and is thus considerably higher was due to a condition after radical prostatectomy, than the reported 10±12% after intracavernous therefore this patient population showed a patient- injection of Alprostadil.5,12 A further important selection-bias. This is in so far of importance, as complication after MUSETM-administration is the patients with an underlying neurologic etiology of provocation of urethral lacerations with temporary their erectile disturbances (damage of cavernous bleeding out of the external urethral ori®ce in 5%.12 nerves) are more likely to respond to Alprostadil, as Although Spivack et al29 assure that these 5% of it was also proven in this trial with ef®cacy-rates of `minor' urethral trauma resolved spontaneously 76.7% in the radical-prostatectomy-group compared without any sequelae for the urethra, it must be to 65.9% in all patients.12,17 Although only respon- argued, that no appropriate investigations like ders of the `in-clinic-titration-phase' were enrolled urethroscopy or urethrography were conducted in in a three months placebo controlled home treat- the long-term follow-up of these patients with ment trial the success-rates after MUSETM-applica- urethral trauma after MUSETM-application. Keeping tion were only 50.4% (2485 out of 4933) compared in mind the fact, that principally each minor to 10.4% after placebo. Similar ef®cacy-rates were urethral trauma may induce an urethral stricture, yielded in the Multi-Center-European MUSETM the statement that in long-term observations after trial.18 In the presented cross-over study the total MUSETM-application such urethral strictures will response-rate in unselected patients with erectile not occur, even in cases with repeated urethral dysfunction amounted to 43% after MUSETM com- bleeding, remains an unproven speculation. Espe- pared to 70% after intracavernous Alprostadil. A cially after the higher MUSETM dosages of 500± subdivision of the responders (ED-score 4 and 5) 1000 mg systemic adverse events attributable to a showed, that only 10% (10 out of 103) of the patients blood pressure decay were encountered in 2±8% had full rigid erections after MUSETM, compared to with syncopes in 0.4±1%.12,29,30 Therefore it seems 48% (49 out of 103) after i.c. Alprostadil. The very important and is also recommended in the majority of the MUSETM-responders had incomplete package insert of MUSETM that the ®rst MUSETM- erections with full tumescence and partial rigidity. application, especially the high dosages has to be These observations are re¯ected by the duplex- performed in the physician's of®ce with blood- sonographic blood ¯ow measurements. Whereas pressure monitoring. The frequently encountered Transurethral Alprostadil with MUSETM H Porst 191 attitude of many physicians to prescribe MUSETM 155: 802±815. without any prior investigations on the patient's 6 Montague DK et al. Clinical guidelines panel on erectile TM dysfunction: summary report on the treatment of organic tolerability of MUSE to the patient in the of®ce erectile dysfunction. J Urol 1996; 156: 2007±2011. must be considered as medical mal-practice. 7 Palmer LS et al. Characterization of cyclic AMP accumulation The rate of persistent ®brotic penile alterations in in cultured human corpus cavernosum smooth muscle cells. J long-term follow up (up to four years) of self- Urol 1994; 152: 1308±1314. 8 Zhang P, Christ GJ, Brink PR, Ney P. PGE -induced alterations injection therapy with Alprostadil ranged in large 1 in maxi-K channel activity in cultured human corporal smooth prospective trials between 5 and 6% and was muscle cells. J Urol 1996; 155 (Suppl) 678A: 1468. reported 1% after MUSETM.28,29,31 Although this 9 Molderings GJ, van Ahlen H, GoÈthert M. Modulation of seems to be in favour of MUSETM it has to be taken noradrenalin release in human corpus cavernosum by into consideration, that MUSETM-follow up-data presynaptic prostaglandin receptors. Int J Impot Res 1992; 4: 29 19. > 18 months are available in only 93 patients. In 10 Kifor I et al. Tissue angiotensin II as a modulator of the own series with more than 30 permanent erectile function. I. angiotensin peptide content, secretion MUSETM-users, three patients developed ®brotic and effects in the corpus cavernosum. J Urol 1997; 157: 1920± periurethral alterations with thickening of the 1925. 11 Padma-Nathan H et al. Hemodynamic effects of intraurethral ventral tunica albuginea of the cavernous bodies Alprostadil: The Medicated Urethral System for Erection and with simultaneous ventral bending of the penis (MUSE1). J Urol 1994; 151: 345A: 469. in two patients. 12 Padma-Nathan H et al. for the MUSE1 Study Group. Quality of life questionnaires have provided Treatment of men with erectile dysfunction with transurethral convincing proof that self-injection therapy with Alprostadil. New Engl J Med 1997; 336: 1±7. TM 13 Wolfson B et al. Intraurethral Prostaglandin E2 cream: a Alprostadil and transurethral therapy with MUSE possible alternative treatment for erectile dysfunction. have a positive impact on quality of life parameters Urology 1993; 42: 73±75. like self esteem, emotional well-being and in¯uence 14 Schmidt AC. Prostaglandin E2 gel: an alternative treatment on partnership.28,32,33 These important positive in- for erectile dysfunction. Int J Impot Res 1994; 6 (Suppl 1): A43. ¯uences on patients and the partnership render both 15 Rozas KP et al. Intraurethral prostaglandin for the treatment of methods indispensable in the therapeutic manage- postprostatectomy impotence. J Urol 1995; 153 (Suppl) 473A: ment of male impotence. The needleless adminis- 977. tration with a very user-friendly application device 16 Florante J, Leyson J. Comparative study between transdermal prompt many patients to prefer MUSETM to self- and transurethral prostaglandin E2 in the treatment of impotence in neurologically impaired patients. J Urol 1995; injection therapy and those patients in whom 153 (Suppl) 482A: 976. MUSETM works reliably at home are very satis®ed 17 Costabile RA et al. on behalf of the VIVUS-MUSE Study with this new therapeutic option. On the other hand Group. Ef®cacy and safety of transurethral alprostadil in the considerably lower ef®cacy of MUSETM com- patients with erectile dysfunction following radical prosta- pared to i.c. Alprostadil exclude the majority of tectomy. J Urol 1997; 157 (Suppl) 364: 1424. 18 Porst H et al. and the European VIVUS-MUSE1 Study Group. 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