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 R Lewis 1 * 1 Medical College of Georgia, Augusta, GA, USA This brief review examines the history of the intraurethral (IU) pharmacotherapy for the treatment of erectile dysfunction (ED). Emphasis is placed on the design, study endpoints and results of a limited number of clinical trials undertaken with PGE 1 -MUSE to demonstrate the ef cacy of this unique delivery system. Next, the theory of the iontophoretic technique of drug delivery is discussed. Clinical data collected while applying these methods are presented, but are thus far limited to treatment of patients with Peyronie's disease. Iontophoresis as a drug delivery alternative may gain popularity with ED patients who fail other types of therapy or in patients with other penile disorders. (2000) 12, Suppl 4, S86±S90. Keywords: pharmacotherapy; electromotive drug delivery; Peyronie's disease; International Index of Erectile Function History of intraurethral therapy The rst published use of an intraurethral (U) medication for erectile dysfunction (ED) was contributed by Wolfson et al in 1983 where they reported on prostaglandin E 2 gel. 1 This was followed in 1984 with a paper by Lazzeri et al regarding the use of IU capsaicin for the treatment of ED. 2 Both were rather limited reports and the exact mechanism whereby the medication was delivered to the corpora cavernosal tissue to produce an erection was not fully understood. The rst commercial attempt to develop a transurethral delivery system for the treatment of ED was proposed by Vivus Inc. (Menlow Park, California). Pivotal studies were performed in the late 1990s and FDA approval was granted in 1997. This product consisted of a semi-solid suppository of alprostadil (PGE 1 ) and a delivery system known as MUSE. The drug was delivered through an applicator approximately 3 cm in length containing the semi-solid suppository of alprostadil. Physicians and scientists working with Vivus described that the action of alprostadil delivered intraurethrally was due to absorption through the urethral epithelium into the corpora spongiosum. Further diffusion of the medication proceeded through venous connections between the spongiosum and cavernosum into the *Correspondence: RW Lewis, Medical College of Georgia, Section of Urology Rm BA-8408, 1120 15th St. Augusta, GA 30912 ± 4050, USA. E-mail: rlewis@mail.mcg.edu corporeal tissue. This was substantiated by studies in 21 patients who received 500 mg of the transurethral alprostadil; subsequent hemodynamic changes within the corpora cavernosa were assessed by color duplex Doppler ultrasonography. 3 Peak systolic velocities were reported to be normal in these 21 patients (ranging from 25 to >30 cm=sec). In that report, however, end diastolic velocities ranged from 8 to 10 cm=sec, indicating that there was a lack of total venous occlusion. Clinical trials of intraurethral therapy Shortly after the approval of PGE 1 ± MUSE, it was found that by using a venous occlusion device around the base of the penis called the ACTIS band, the erectile response obtained with IU alprostadil could be enhanced. Subsequently, pivotal studies were performed in 232 patients (see below) to verify this enhancement. The differences between the response rate recorded in the original trials (without the ACTIS band) to those obtained with the ACTIS band suggested that there was enhancement of drug effect when used in conjunction with the venoocclusive device. This enhancement may have improved the subsequent clinical responses seen by physicians who prescribed the agent for their patients. In the pivotal FDA trials, 4 only 66% of the patients responded to in-clinic titration. Of the 873 patients who then tried home use (which was

allowed only if the patient had a good response in the of ce titration test), 64.9% obtained success at home. Although the overall success rate was thus only 43% (66% 6 64.9%) in this original group of patients, the article stressed the `greater than 60% success' with ED of all etiological types. Most physicians who prescribe the agent for patients in their practice were obtaining results of 30 ± 40% or less. 5 In spite of the fact that these data were clearly available in the original article, 4 they were not commented on, even in an editorial section. During home treatment, penile pain occurred in 32.1% of patients receiving the active ingredient alprostadil (10.8% of all applications in all patients). In the clinic titration studies, hypotension occurred in 3.3% of men and syncope in 0.4% after use of the medicated IU system. There was minor IU trauma in 5.1% of the applications. During the home trials, however, only 1.9% of patients (nine total; four dropped out because of pain) dropped out of the study because of adverse affects of drug compared to 0.6% on placebo. A subset of the original patients described in the article 4 were patients who had previously failed to be successful with intracavernosal injection therapy. 6 Fifty-eight percent of these patients had erections suf cient for intercourse with the use of MUSE. In the pivotal study with PGE 1 ±MUSE and the veno-occlusive device, 89% of patients had success in the clinic and then tried intercourse at home with the IU suppository. Seventy-two percent of those patients were able to have successful intercourse at home, demonstrating an overall success rate of 62%. 7 This group of patients were categorized as having one of four degrees of ED de ned by the International Index of Erectile Function (IIEF) penile erection subset scale (maximum score 30), ie, mild, mild to moderate, moderate, or severe. Patients who had mild ED (score of 19 ± 24=30) had a 91% response of erection at least once during home use; those with mild to moderate (score of 13 ± 18=30), 97%; those with moderate (score of 7 ± 12=30), 74%; and those with severe (score of 0 ± 6=30), 59%. Penile pain occurred in 38.9% of this group and 16.2% described urethral pain or burning. There was minor urethral spotting or bleeding in 9.2% of the patients and testicular pain in 5.9%. In the initial studies conducted for FDA approval, there was a subset of patients (n ˆ 415), who had also tried alprostadil alone compared to alprostadil=prazosin combinations. The presence of the alpha-1 blocker, prazosin, produced better erections than alprostadil alone for all dose levels of drug. 8 A recent pivotal study supporting the FDA submission for approval of a combination of 125 mcg alprostadil and 500 mcg prazosin (Alibra) has been completed and is currently being evaluated by the FDA. The results of this trial with the combination agent have not, as yet, been released for publication. R Lewis There have been two studies published that compare MUSE with intracavernous PGE 1. The rst report was by Porst in 1997, 9 in which 103 consecutive ED patients who suffered from the disorder for six months or greater, were given of ce trials with injectable alprostadil (10 mg as a rst injection) versus MUSE (500 mg as rst dose) in random order. 9 The erectile response was rated from 1 to 5, exactly like the original MUSE pivotal studies. Duplex ultrasonography was performed in all patients who received each of the medications. Forty-eight percent of patients who received injectable intracavernosal alprostadil had an erectile response score of 5; 22% had a score of 4, for a total positive response rate of 70%. Similar responses were obtained in those receiving MUSE: 10% had a score of 5, 33% had a score of 4, for a total response of 43%. The dose producing the best erection from intracavernosal injectable alprostadil was 20 mg in 65% of patients and 10 mg in 28% of the patients. For those who responded to MUSE, 56% required the 1000 mg IU suppository and 21% responded to the 500 mg suppository. Ultrasonographic measurement of the intracavernosal arteries revealed that there was a slight, but non-signi cantly higher peak systolic velocity in the injectable intracavernosal alprostadil compared to MUSE. However, these patients with injections did have a signi cant lower end diastolic velocity. Interestingly, end diastolic velocities after MUSE administration were approximately 8 cm=sec, similar to the original data published in the studies sponsored by Vivus. 3,9 In 103 patients described by Porst, 37.9% estimated the intracavernosal injectable alprostadil superior and 15.5% felt that the injectable intracavernosal alprostadil was inferior to the MUSE system. Forty-seven percent described no difference between the two. The second comparative report about MUSE and injectable alprostadil was a multi-institutional study reported by Shabsigh et al in early 2000. 10 In this study, 111 men with ED for at least 6 months with a mean age of 59.2 y (range 38 ± 79 y), participated in two phase crossover study in which the two agents were administered in random order. The rst phase consisted of an in-of ce titration for 1 ± 14 days followed by a second phase of at-home treatment lasting three months. This study compared injectable Edex (alprostadil alfadex) versus MUSE. Patients in the MUSE group were allowed to optionally use the ACTIS occlusive band. The inof ce injection phase consisted of 95 patients who underwent titration with both agents. The erection grading system used during the in-of ce titration considered an erection score of 3 to be capable for intercourse. Edex received a grade 3 erection score in 61.2% of erections as judged by the physicians and 66.3% of erections as judged by the patient. Results for the MUSE system were 20% and 26.3% when physicians and patients, respectively, graded the treatment. After the home treatment phase 68 S87

S88 RLewis patients were analyzed. The most frequently used dose during in-home use for Edex was 40 mg (44.1%), and for MUSE was 1000 mg (86.5%). During the in-home phase, there were 315 Edex selfinjections administered and 313 applications of the MUSE system (33% used ACTIS with MUSE). Of the 315 Edex injections, 260 (82.5%) resulted in successful intercourse; of the 313 applications of MUSE, 166 (53%) had successful intercourse. Out of 68 patients, 92.6% and 61.8% reported having at least one successful erection with Edex and MUSE, respectively. In the same 68 patients, 51 (75%) used Edex successfully for erections in 75% of all applications and 25 (36.8%) used MUSE successfully 75% of the time. P values were less than 0.0001 in favor of Edex over MUSE in these last two comparisons. Using questions 1 through 5 and 15 from the IIEF, the mean baseline score was 9.2 (total maximum points 30) for the 68 patients who participated in the study. The score was increased to a mean of 25.3 with the use of Edex and with MUSE, to 17.3 (P < 0.001). Sixty-nine percent of the patients and 63% of the partners preferred Edex for treatment at the end of the study while only 10% of patients and 10% of their partners selected MUSE. The remainder of patients and partners had no preference. Forty-two patients chose Edex as their continued therapy and 12 chose MUSE. In summary, based upon these two comparative published studies, between 10 and 15% of patients would still prefer MUSE over intracavernosal injection therapy. Some enhancement of response of the IU suppository may be accomplished using the veno-occlusive band, ACTIS. There are a number of patients who experience signi cant penile pain when using PGE 1 whether it is delivered intraurethrally or intracavernosally. There is some suggestion from the original pivotal studies in which various combinations of alprostadil and the alpha-1 blocker, prazosin, were used; that a better response was achieved with the combination agent. It remains to be seen just how many patients will select the IU suppository when presented with the various treatments for ED. Response to an in-of ce trial will usually range from 40 to 60% and subsequent success at home (in >75% of the applications) will range between 30 and 40%. Although an oral agent would most certainly be the rst choice for any patient with ED, if oral therapy is unsuccessful, there might be a subset of patients who will prefer IU delivery. This type of therapy might continue to be viable, especially if new agents are developed with fewer side effects, such as pain on application, and better response rates. Iontophoretic drug delivery methods Iontophoresis or electromotive drug administration (EMDA) is a process that involves the transport of ionic (charged) molecules into tissue by passing a direct electric current through an electrolyte solution containing the ionic molecules to be delivered. 11 Several reviews have been published which discuss the historical development and principles behind iontophoresis or EMDA therapy 11 ± 13 Brie y, positively charged ions are driven into the target tissue by the anode (positive electrode) while negatively charged ions are driven by the cathode (negative electrode). 11 The variables which affect transport of drugs to the target tissues and uids are drug concentration, electrical charge of the drug, molecular size of the drug, and resistance of various tissues and=or uids. Movement of ions is dependent on a linear sum of the effects of ion concentration and electrical eld (Nernst-Planck equation). The number of ions transported into a particular tissue is a product of the applied current and time. The magnitude of most currents that are applied is between 1 and 75 ma. Ions of lower molecular weight are more mobile and the degree of ionization of the drug in solution is ph dependent. Delivery of drug through a tissue is highly dependent on the resistance of the tissue. Most deep tissues of the body have 50 ± 75 O of resistance while the stratum corneum of skin has a high resistance of 1000 O. A higher electrical current can enhance delivery of drug, but thermal damage to tissue through which the current passes is a limiting factor. The degree of heat developed depends upon the amount of resistance present in the tissue. A direct steady current usually causes skin irritation due to continuous electrical polarization in the high electric barriers in the skin. 12 Pulse generating devices have obviated the concern about irreversible skin trauma. Iontophoretic therapy of Peyronie's disease In the practice of urology, the primary use for iontophoresis has been for the treatment of Peyronie's disease (PD). Most of the reports are anecdotal and describe its use in single patients or very small groups of patients without controls. The rst report appeared in 1967, and described the treatment of PD by iontophoresis using C 21 esteri ed glucocorticoids. 14 Typical treatment in these 12 patients consisted of two 6-min applications at 4 ± 8 ma with an average of 12 ± 13 treatments given in intervals three times per week. In all 12 patients, the plaque became softer but did not disappear and in ve patients, there were de nite signs of regression of the lesion. One patient showed no improvement other than resolution of pain. Overall, iontophoresis appeared to favorably in uence the symptomatology of PD in these patients. Another report appeared of a single case using iontophoresis with 0.5% hydrocortisone ointment. 15 In 1994, there was a report of

iontophoretic treatment of PD in three patients with mature disease. 16 Their treatment consisted of three, 20-minute sessions weekly for two weeks with 1% cortisone cream applied directly over the penile plaque. A positive electrode was placed above the application site of cortisone cream and a negative electrode was placed at a neutral site (eg thighs, abdominal wall). A current of 3 ± 5 ma was applied, depending upon the patient's tolerance. These three patients were successfully treated with iontophoresis in spite of having mature PD. The authors of this report commented that controlled studies should follow. In the only controlled study of iontophoresis for the treatment of PD, Montorsi et al reported results in 40 patients. 17 Patients received either placebo treatment or a combination of lidocaine, orgotein, and dexamethasone. Treatment current was 3 ma three times a week for three weeks in 20-min sessions. In patients receiving active drug the plaque disappeared in 19 of 40 (47%), signi cantly decreased in 13 of 40 (32%), and remained unchanged in 8 of 40 (20%). Twenty- ve of 40 (62%) had improvement in angulation and in 15 of 40 (38%), angulation was not improved. Pain resolved in all patients presenting with this symptom. The latest report of iontophoretic treatment for PD appeared recently (January, 2000). 18 In this report, 100 patients (average age 53.6 y) were treated between 1994 and 1998. These patients were administered 8 mg dexamethasone and 40 mg lidocaine for painful plaques or 8 mg dexamethasone and 5 mg of verapamil for painless lesions. The positive verapamil electrode was connected to a 5 6 7 ml plastic self-adhesive receptacle containing the medication. A cathode was attached to a skin electrode on the lower abdomen. The current generator was a Physionizer 30 (Physion, Mirandola, Italy) that delivered a pulsed direct 2500 Hz current of 5 ma for 20 min. There were between three and 10 weekly treatments. Pain was eliminated in 38 of 60 (63%) patients having this symptom and signi cantly improved in 20 of 60 (23%). In patients who presented with de ned cavernous plaques, these were reduced in 31 of 79 (39%) and totally disappeared in 11 of 79 (14%). In 33 of 79 (42%) patients with a de ned plaque, the plaque was unchanged and in four of 79 (5%), the plaque increased. With regard to penile deviation, there was complete straightening or a greater than 30 degree improvement in curvature in 12 of the 77 (16%) patients in which penile deviation was documented. Less pronounced improvement was reported in 16 of 77 (21%) and no change in penile deviation occurred in 43 out of 77 (55%). Angulation actually increased in six of 77 (8%) patients. There was restoration of erectile function in seven of the 23 (39%) of patients who complained of ED associated with PD. R Lewis Conclusion Iontophoresis has primarily been described for the treatment of PD. Its use as a drug delivery system for ED has yet to be reported. Certainly, the characteristic resistance of the tunica albuginea would have to be de ned and overcome for delivery of drug to be feasible through this tissue into the corpora cavernosa. Unique location of electrodes delivering medication might enhance drug delivery into the corpora cavernosa. Another use for iontophoresis has been suggested by Wong and Grif th as a possible treatment for prosthetic infection, particularly in treating the glycoprotein layer associated with infected prosthesis. 11 Thus, iontophoresis presents a potential area of development for drug delivery in patients with ED and other penile disorders. References 1 Wolfson B et al. Intraurethral prostaglandin E-2 Cream: a possible alternative treatment for erectile dysfunction. Urology 1993; 42: 73 ± 75. 2 Lazzeri M et al. Intraurethrally infused capsaicin induces penile erection in humans. Scand J Urol Nephrol 1994; 28: 409 ± 412. 3 Tam P et al. Hemodynamic effects of transurethral alprostadil measured by color duplex ultrasonography in men with erectile dysfunction. J Urol 1998; 160: 1321 ± 1324. 4 Padma-Nathan H et al. Treatment of men with erectile dysfunction with transurethral alprostadil. New Engl J Med 1997; 336: 1±7. 5 Fulgham PF et al. Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting. J Urol 1998; 160: 2041 ± 2046. 6 McVary KT et al. Ef cacy of transurethral alprostadil in patients who failed prior intracavernosal injection therapy. Int J Impot Res 1996; 8: 146, Abst D97. 7 Lewis RW, Weldon K, Nemo K. Combined use of transurethral alprostadil an adjustable penile constriction band in men with erectile dysfunction: results from a multicenter trial. Int J Impot Res 1998; 10: S49, Abst 365. 8 Lewis RW et al. A comparison of transurethral alprostadil and alprostadil=prazosin combinations for the treatment of erectile dysfunction (ED). J Urol 1997; 159: Abst 703, 181. 9 Porst H. Transurethral alprostadil with MUSE (medicated urethral system for erection) vs intracavernous alprostadil Ð a comparative study in 103 patients with erectile dysfunction. Int J Impot Res 1997; 9: 187 ± 192. 10 Shabsigh R et al. Intracavernous Alprostadil Alfadex is more ef cacious, better tolerated, and preferred over intraurethral alprostadil plus optional ACTIS: a comparative, randomized, crossover, multicenter study. Urology 2000; 55: 109 ± 113, 11 Wong HY, Grif th DP. Iontophoresis in medicine: possible applications in urology. Minim Inva Ther 1993; 2: 51 ± 57. 12 Singh J, Maibach HI. Topical iontophoretic drug delivery in vivo: historical development, devices and future perspectives. Dermatology 1993; 187: 235 ± 238. 13 Gurpinar T, Truongld, Wong HY, Grif th DP. Electromotive drug administration to the urinary bladder: An animal model and preliminary results. J Urol 1996; 156: 1496 ± 1501. S89

S90 RLewis 14 Rothfeld SH, Murray W. The treatment of Peyronie's disease by iontophoresis of C 21 esteri ed glucocorticoids. J Urol 1967; 97: 874 ± 875. 15 Kahn J. Use of iontophoresis in Peyronie's disease: a case report. Phys. Ther 1982; 62: 995 ± 996. 16 Fishman IJ, Wong HY, Grif th DP. Case report. Iontophoretic delivery of steroids in the treatment of Peyronie's disease: case reports of three successful outcomes. Minim Invas Ther 1994; 3: 121 ± 124. 17 Montorsi F et al. Transdermal electromotive multi-drug administration for Peyronie's disease: a randomized, doubleblind, placebo-controlled, partial crossover study. J Urol 1995; 153: 472A, Abstr 973. 18 Reidl CR et al. Iontophoresis for treatment of Peyronie's disease. J Urol 2000; 163: 95 ± 99. Appendix Open discussion following Dr Lewis' presentation Dr Wessell: Why doesn't the end diastolic velocity drop down to zero with MUSE? Dr Lewis: For some reason, you're not getting as much smooth muscle relaxation from intraurethral delivery as you are with intercavernosal delivery. I'm impressed that the end diastolic velocity in Dr Porst's of ce measurements in the original 21 patients is about the same level. Dr Eid: I have three comments. Firstly, when I participated in the clinical trials with MUSE very early on, the product was a combination of prostaglandin E1 and prazocin. Of 61 patients treated, three passed out. Two of the 61 obtained an erection, so we knew it was not effective. Secondly, in clinical trials, the intercourse endpoint reported on was `at least once', but if you asked how many had intercourse more than once, the success rate dropped dramatically and ef cacy wasn't 63%. Thirdly, the endpoint of a tumescent penis was counted as a success if it scored 3 out of 5. But we were originally told that a success was at least a 4 or a 5. They changed the endpoint. Dr Lewis: That shows that you can develop endpoints to make anything look good and that's a problem. The original studies looked at combination therapy, but when they began to see syncope episodes, they were stopped. Dr Sharlip: Data that comes from an industrysponsored study has certain natural prejudices, but it's equally our fault for not seeing through that. We are the ones who have to protect our patients and we need to be vocal. Dr Lewis: Yes, and that's what was lacking, a good editorial comment on that Journal of Urology article on MUSE, because the data is there. The data wasn't commented about in the discussion section. And if you go back and look at Caverject, Viagra and MUSE, not one endpoint is the same in the New England Journal of Medicine articles; not one endpoint is the same for three major drugs that have been introduced for erectile dysfunction. We've got to get some endpoints that are consistent. Dr Wessell: Is there anybody here that prescribes MUSE without the use of the ACTIS? (5 or 6 hands were raised). So it works without ACTIS? Dr Speaker: It does work without ACTIS in certain patients but ACTIS enhances the results. Dr Sharlip: It's a small percentage, but I have patients, including two post-radical prostatectomy patients, who have a great response. The reason it doesn't work as well as intercavernous injections, is that the number of micrograms of drug that gets into the corpus cavernosum is less. It's at least possible with a skin enhancing agent that you may be able to apply enough drug to the glans penis so that it penetrates the corpus spongiosum.