Salvage of Sildenafil Failures With Bremelanotide: A Randomized, Double-Blind, Controlled Study

Mohammad Reza Safarinejad* and Seyyed Yousof Hosseini From the Urology and Nephrology Research Center, Shaheed Modarress Hospital, Shaheed Beheshti University of Medical Sciences, Tehran, Iran

Purpose: We evaluated the safety and efficacy of intranasal bremelanotide in men with erectile dysfunction who did not respond to sildenafil. Materials and Methods:A total of 342 married men (28 to 59 years old) with erectile dysfunction who did not respond to sildenafil were randomly assigned to receive 10 mg bremelanotide as an intranasal spray (group 1, 172) 45 minutes to 2 hours prior to sexual stimulation, or a similar regimen of placebo (group 2, 170). Patients were asked to use at least 16 doses/attempts at home. They underwent preliminary assessment, including medical and sexual history, and self-administered International Index of Erectile Function. The efficacytreatments o f 2 was assessed every 4 attempts during treatment and at the end of study, using responses to International Index of Erectile Function, and evaluation of mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects. Results: Positive clinical results were seen in 51 (33.5%) patients in the bremelanotide group compared with 13 (8.5%) patients in the placebo groupϭ 0.03). (p Patients in the bremelanotide group reported significantly greater intercourse satisfaction than those in placebo groupϭ 0.03). (p More drug related adverse effects occurred in the bremelanotide group (p ϭ 0.01). Conclusions: Bremelanotide can be an alternative treatment for erectile dysfunction with a potentially broad patient base. Further studies with different dosages and treatment regimens are necessary to draw final conclusions on the efficacy of this drug in erectile dysfunction. Key Words: receptors, ; erectile dysfunction; drug therapy; sildenafil; PT-141

rectile dysfunction has been estimated to affect,Most to of the research efforts toward the treatment of ED some degree, 52% of men 40 to 701 Theyears haveold. targeted the peripheralmechanisms of penile erec- E launch of orally administered phosphodiesterase tion.type The administration of for the treat- 5 inhibitors has had a revolutionary effect on the menttreatment of ED has demonstrated the possibility of enhancing of ED. Sildenafil citrate, a PDE-5 inhibitor, selectivelypenile in-erection by acting elsewhere than on corpus caver- hibits cyclic guanosine monophosphate specific PDE typenosum 5, smooth muscle cells.7 Melanocyte stimulating hor- leading to increased cyclic guanosine monophosphate monelevels and related regulate a diversity of 2 which result in muscle relaxation and penile tumescence.functions as mediated through a multitude of MC recep- Results of extensive multicenter international clinical tors.trials Most interesting was the relatively recent discovery have demonstrated superior efficacy of sildenafil to thatplacebo a MC regulates sexual function in8 PT-141humans. 3 with an overall dose dependent response rateIt ofhas 78%(bremelanotide),. a cyclic, heptapeptidemelanocortin ana- been determined that, up to 50% of subjects who log,receive is anthe active metabolite of Melanotan-II.9 It is erectogenic 4 sildenafil do not respond adequately to Marketingtherapy. in men by an action believed to occur C3-Randat central M data worldwide showed that dropout rates for sildenafil are10 5 MC4-R. Diamond et al reported that the erectile re- as high as 50% of patients Amongtreated. other factors, sponse induced by co-administration of PT-141 and silde- side effects such as severe , flushing, and visual nafil is significantly greater than the response elicited by disturbances contribute to the reasons for discontinuation. administration of sildenafil alone.11 In another study PT- In addition, in a study by El-Galley et al, there was a 141 was evaluated following intranasal administration12 . possible tachyphylaxis effect with sildenafil.6 Of the patients Erectile response induced by PT-141 was statistically sig- who were followed for 2 years 20% had to increase the nificant, compared to placebo. This new chemical entity sildenafil dose to have the same effect and 17% discontinued has been evaluated in phase II clinical trials studying the use due to loss of efficacy. efficacy and safety profile of varying doses of in men experiencing ED. Doses ranging from 0.3 to 10 mg were administered to healthy male subjects without visual sex- Submitted for publication July 1, 2007. ual stimulation, resulting in a statistically significant * Correspondence: P.O. Box 19395-1849, Tehran, Iran (telephone: 13 0098 21 22454499; FAX: 0098 21 22456845; e-mail: safarinejad@erectile response at doses greater than 1 mg. In addi- urologist.md). tion, administration of either 4 or 6 mg subcutaneous See Editorial on page 819. bremelanotide, in association with visual sexual stimula-

0022-5347/08/1793-1066/0 1066 Vol. 179, 1066-1071, March 2008 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.10.063 BREMELANOTIDE FOR TREATMENT OF FAILURE 1067 tion, to patients with moderate or severe ED who report Inclusion/Exclusion Criteria an inadequate response to sildenafil, resulted in a signifi- None of the patients had received other treatment for male cant erectile response compared to the placebo response.13 ED for at least 4 weeks before the start of the study. Patients Therefore PT-141 is a promising candidate for further were eligible for inclusion in the study if they were aged 18 evaluation as a treatment for male ED. In March 2006 the years or older, were nonresponders to sildenafil mono- United States Adopted Names (USAN) Council and the therapy and had medically documented ED of at least 6 WHO have approved the generic name bremelanotide for months duration. The patients had to be in a stable relation- PT-141. To our knowledge this is the first large scale, ship with his wife for at least the previous 6 months. at-home evaluation of bremelanotide. Exclusion criteria were penile anatomical defects; a pri- mary diagnosis of another sexual disorder; use of psy- chotropic and antidepressant medication, and serious rela- MATERIALS AND METHODS tionship problems; poorly controlled diabetes mellitus; un- Study Design controlled congestive or ischemic heart disease, or renal or From March 2004 to December 2006 a total of 446 married liver impairment; history of or drug abuse; spinal men (28 to 59 years old) with ED and their wives were cord injury; history of prostate cancer; neurological disor- enrolled in this study (without sponsorship). They were re- ders that cause ED; and those unlikely to be available for ferred to 1 urologist (MRS) from primary care physicians or followup. addressed themselves disappointed by the results of silde- nafil. The diagnosis of ED was established according to the National Institutes of Health statement on ED.14 All sub- Medical Treatment jects gave their written informed consent in accordance with Eligible patients were randomly assigned to double-blind, the Declaration of Helsinki. The Human Ethics Committee fixed dose treatment with either bremelanotide or placebo. approved the study protocol. All patients were given a silde- Assignment to treatment group was performed using an nafil instruction/safety sheet prior to including the study. interactive voice response system, which followed a random- The instruction sheet emphasized the timing of sildenafil ization table generated by the method of random permuted administration (45 minutes to 2 hours prior to sexual stim- blocks. Group 1 (172) was given 10 mg bremelanotide as an ulation) as well as the absolute need for sexual stimulation, intranasal spray 45 minutes to 2 hours prior to sexual stim- such as visual stimulation, foreplay and hugging. In addi- ulation. Group 2 (170) received a similar regimen of placebo. tion, the instruction sheet stressed that sildenafil should be Patients were asked to use at least 16 doses/ used 2 to 3 hours after a low fat meal. Finally, the sheet also attempts at home, but not to exceed more than 1 attempt per emphasized that outcomes tend to get better after 6 to 8 day. All of the men were asked not to consume alcoholic attempts and success is often dose dependent. The starting drinks within 6 hours of sexual activity. dose in all patients was 50 mg. They were instructed to rapidly increase the dose from the 50 mg to 100 mg after 1 attempt if the initial treatment was not satisfactory and Outcome Measures there were no adverse reactions, but not to exceed more than All patients were seen with their wives and interviewed 1 tablet per day. Patients were asked to use at least 12 about sexual activity and erectile function. The effect of tablets/attempts at home. Outcome measures were assessed treatment was assessed every 4 attempts during treatment, using a global assessment questionnaire (“Did this treat- evaluating changes in IIEF and responses to the questions ment improve your erections?”). The effect of treatment was from the IIEF question 3, “When you attempted sexual in- assessed every 2 weeks during a 16-week treatment period. tercourse, how often were you able to penetrate your part- Of the 446 patients reeducated 58 (13%) responded to silde- ner?” and question 4, “During sexual intercourse, how often nafil and were therefore excluded from the study. A total of were you able to maintain your erection to completion of 388 men who were nonresponders to sildenafil entered the intercourse?” Responses to the 2 questions were rated on a study (mean age 42.5 years, range 28 to 59) with a mean scale ranging from 1 to 5, with 5 response options 1—almost duration of penile ED of 2.4 years (range 1.5 to 6). The study never/never, 2—a few times (much less than half the time), was not advertised, and no remuneration was offered. 3—sometimes (approximately half the time), 4—most times (much more than half the time) and 5—almost always/al- ways. The 5 separate response domains of erectile function, Evaluations orgasmic function, sexual desire, intercourse satisfaction All patients underwent preliminary assessment, including a and overall satisfaction were also used in the assessment of medical and sexual history, physical examination, a resting efficacy. Each patient also responded to a global efficacy 12-lead ECG, structured interview diagnostic of mental and question (“Did the treatment improve your erections?”), and physical disorders, and self-administration of the IIEF.15 maintained an event log, in which was recorded the date of To be able to exclude organic , fasting the medication taken, the presence of sexual stimulation, blood glucose level, urinalysis, complete blood count, sex the hardness of erections on a 4-point scale, the number of hormones and prolactin levels were measured. When in- attempts at sexual intercourse and the number of attempts dicated, other tests were used to establish the diagnosis of that were successful. All patients were asked to indicate vasculogenic and neurogenic ED, including penile color sexual satisfaction on a scale of 0 to 5 as proposed by Kim duplex Doppler ultrasonography before and after intra- and Paick, with 0 being extremely dissatisfied and 5 extremely cavernous injection of 20 ␮g , pudendal satisfied.16 None of the patients underwent formal psychosex- nerve conduction test and impaired sensory evoked poten- ual counseling. Adverse events were recorded at each visit. tials studies. Other secondary efficacy parameters included successful at- 1068 BREMELANOTIDE FOR TREATMENT OF SILDENAFIL FAILURE tempt at sexual intercourse, mean intercourse frequency and TABLE 1. Patient demographics quality of life (QOL)17 assessment. Bremelanotide Placebo Safety Assessments Mean age (range) 42.0 (28–59) 43.0 (28–59) Safety was assessed by monitoring the vital signs and changes Mean yrs ED (range) 2.2 (1.5–6.3) 2.6 (1.6–5.7) No. ED etiology (%): in the physical examination findings, clinical laboratory data, Arteriogenic 58 (33.7) 60 (35.3) and electrocardiogram evaluations and reported adverse Mixed vasculogenic 45 (26.2) 47 (27.6) Psychogenic 12 (7) 13 (7.6) events. Veno-occlusive dysfunction 46 (26.7) 45 (26.5) Corporeal fibrosis 9 (5.2) 7 (4.1) No. concomitant risk factors (%): Statistical Analysis Diabetes mellitus 24 (14) 23 (13.5) The study sample size of 446 patients was powered for a Cigarette smoking 58 (33.7) 58 (34.1) difference of approximately 1 standard deviation between Hypercholesterolemia 45 (26.1) 44 (25.9) 37 (21.5) 38 (22.3) the bremelanotide and placebo groups with a statistical Ischemic heart disease 25 (14.5) 23 (13.5) power of 85% (␤ ϭ 0.15) and assuming an overall 25% All values p not significant. dropout rate. Comparison of sexual satisfaction rates of pa- tients and their wives, and comparison of the incidence of side effects were tested using the chi-square test with Yates the groups (p ϭ 0.08). The etiology of erectile dysfunction correction or Fisher’s exact, when necessary. The Mann- was arteriogenic in 118 (34.5%) patients, psychogenic in 25 Whitney test was used to compare quantitative variables. All (7.3%), cavernous venous leakage in 91 (26.6%), mixed vas- time-course data were analyzed by 2-way ANOVA for repeated culogenic in 92 (26.9%) and secondary to corporeal fibrosis in measures. Statistical analysis was performed using the com- 16 (4.7%). Of the men 47 (13.7%) had diabetes mellitus, 116 puter statistical package SPSS®/4.0 and SAS®/6.4. (33.9%) were cigarette smokers, 89 (26%) had hypercholes- terolemia, 75 (21.9%) had hypertension and 48 (14%) had RESULTS ischemic heart disease. Patient Disposition/Demographics Of 388 nonresponders 342 met inclusion and exclusion cri- Efficacy teria and agree to participate in the study. Of recruited Overall 51 (33.5%) and 13 (8.5%) patients who took subjects 304 (89%) completed the whole randomized trial bremelanotide and placebo, respectively, were responsive to (152 of 172 in the bremelanotide group and 152 of 170 in the treatment (able to attain and maintain an erection sufficient placebo group) (see figure). Mean patient age was 42.0 years to allow sexual intercourse) (p ϭ 0.03). (range 28 to 59) in group 1 and 43.0 (range 28 to 59) in group Treatment with bremelanotide was associated with sig- 2(pϭ 0.08). At baseline the study and placebo groups were nificantly higher scores for question 3 and question 4 than similar in demographics, clinical characteristics and risk baseline (p ϭ 0.02) (table 2). For question 3 the mean score factors (table 1). There were 38 patients (11%) who did not was 2.8 for patients in the bremelanotide group compared complete the study, 18 because of a lack of effects (9 in each with 2.0 for those in placebo group, which represent in- group), 8 adverse effects (5 in the bremelanotide group, 3 in creases from baseline of 55.5% (mean score at baseline, 1.8) the placebo group) and 12 lost to followup (6 in each group). and 11.1% (mean score at baseline, 1.8), respectively. For The difference in dropout rates was not significant between question 4 the mean score was 3.1 (72.2% increase from baseline mean score of 1.8) for the bremelanotide group compared with 2 (17.6% increase from baseline mean score of 1.7) for the placebo group. Of the patients 33% reported at least 1 successful attempt at sexual intercourse in the bremelanotide group compared with 8.2% successful at- tempts during placebo treatment (p ϭ 0.02). The remaining 13 questions assessing other aspects of male sexual function showed significant improvements for the bremelanotide group compared with the placebo group (p ϭ 0.01) (table 3). Time-course data analysis showed that erection was achieved within 1 hour after administration of bremela- notide in 86% of subjects. Of the patients 11% achieved erection within 2 hours. Erections occurred approximately 31 minutes after administration of bremelanotide. Mean duration of sufficient rigidity for penetration (more than 80%) in patients with mild, moderate and severe ED treated was 18, 13, and 10 minutes, respectively, compared to 6, 4 and 2 minutes after administration of placebo (p ϭ 0.01). The mean pretreatment intercourse frequency was 1.2 per week for bremelanotide compared to 1.3 per week for placebo. The mean intercourse frequency at the end of trial was 2.2 and 1.4 for bremelanotide and placebo, respectively (p ϭ 0.03). Baseline and end of trial mean intercourse sat- Study design isfaction domain values of the IIEF were 11, 11 and 16, 10 in BREMELANOTIDE FOR TREATMENT OF SILDENAFIL FAILURE 1069

TABLE 2. IIEF questions 3 and 4 Mean (SE) Question 3 Score Mean (SE) Question 4 Score Age Groups (yrs) Baseline Final p Value Baseline Final p Value

Bremelanotide: 28–34 1.8 (0.2) 3.0 (0.2) 0.01 1.9 (0.19) 3.2 (0.2) 0.01 35–40 1.9 (0.2) 2.9 (0.18) 0.02 1.8 (0.2) 3.2 (0.21) 0.02 41–50 1.8 (0.18) 2.8 (0.21) 0.02 1.8 (0.19) 3.0 (0.19) 0.02 51–59 1.7 (0.21) 2.7 (0.2) 0.03 1.7 (0.2) 3.0 (0.2) 0.03 Placebo: 28–34 1.8 (0.19) 2.2 (0.18) 0.8 1.8 (0.2) 2.2 (0.2) 0.08 35–40 1.9 (0.21) 2.1 (0.21) 0.8 1.8 (0.19) 2.1 (0.21) 0.08 41–50 1.8 (0.2) 1.9 (0.19) 0.1 1.9 (0.21) 1.9 (0.19) 0.09 51–59 1.7 (0.2) 1.8 (0.2) 0.1 1.7 (0.2) 1.8 (0.2) 0.1

groups 1 and 2, respectively. Patients in the bremelanotide ported treatment related adverse events. The most common group reported significantly greater intercourse satisfaction in the bremelanotide group were (22, 12.8%), flush- than those in placebo group (p ϭ 0.03). Bremelanotide also ing (18, 10.5%), sweating (16, 9.3%), lower back pain (12, 7%) increased statistically significant sexual satisfaction scores and taste disturbance (8, 4.7%). Five (2.9%) patients (p ϭ 0.03) (table 4). Mean total QOL scores were similar dropped out of the study because of side effect in the bre- between groups at baseline. Throughout the study changes melanotide group, namely nausea in 4 and flushing in 1. in QOL were generally moderate but were consistently bet- Three patients (1.9%) dropped out of the study because of ter in subjects who received bremelanotide vs placebo, side effect in the placebo group (worsening of erectile func- reaching significance at the end of trial (p ϭ 0.01). tion). All adverse events (except nausea) were mild, self- A response was achieved by 34.2% of patients with arte- resolving and of short duration. No clinically significant riogenic erectile dysfunction, 24.2% with cavernous venous changes were noted in endocrine status, clinical chemistry, leakage and 37.8% with mixed vasculogenic erectile dysfunc- hematology and urinalysis tests or physical examinations. tion. The responses were significantly higher for patients with psychogenic ED (78%). None of the patients with cor- DISCUSSION poreal fibrosis had response to bremelanotide. PDE-5 inhibitors are ineffective in a significant number of Safety patients, are not tolerated by some patients and are contra- More adverse effects were associated with bremelanotide indicated in patients taking organic nitrates. Therefore, treatment (p ϭ 0.01) (table 5). There were 28 (16.3%) pa- identification of alternative treatments for ED is necessary. tients on bremelanotide and 11 (6.4%) on placebo who re- Penile erection involves a coordinated interaction of the

TABLE 3. Questions 1, 2 and 5 to 15 of IIEF

Mean Score Bremelanotide Mean Score Placebo Overall Treatment Question Baseline Final* p Value Baseline Final* p Value† p Value‡

1. How often were you able to get an erection 2.0 3.0 (0.2) 0.02 2.1 2.0 (0.2) 0.10 0.01 during sexual activity? 2. When you had erections with sexual 1.8 3.0 (0.2) 0.02 1.8 1.9 (0.2) 0.68 0.01 stimulation, how often were your erections hard enough for penetration? 5. During sexual intercourse, how difficult was it 1.4 2.8 (0.2) 0.02 1.4 1.6 (0.2) 0.20 0.01 to maintain your erection to completion of intercourse? 6. How many times have you attempted sexual 2.1 3.6 (0.2) 0.01 1.7 2.0 (0.2) 0.1 0.01 intercourse? 7. When you attempted sexual intercourse, how 1.8 3.5 (0.3) 0.01 1.6 1.8 (0.3) 0.41 0.01 often was it satisfactory for you? 8. How much have you enjoyed sexual 1.8 3.7 (0.2) 0.01 1.7 1.9 (0.2) 0.70 0.01 intercourse? 9. When you had sexual intercourse, how often did 2.7 3.6 (0.2) 0.02 2.7 3.3 (0.2) 0.50 0.02 you ejaculate? 10. When you had sexual intercourse, how often did 2.6 3.8 (0.2) 0.02 2.6 3.1 (0.3) 0.52 0.03 you have the feeling of orgasm or climax? 11. How often have you felt sexual desire? 2.6 3.6 (0.2) 0.02 2.5 2.6 (0.2) 0.70 0.02 12. How would you rate your level of sexual desire? 2.2 3.3 (0.1) 0.02 2.2 2.4 (0.1) 0.66 0.02 13. How satisfied have you been with your overall 1.7 2.8 (0.2) 0.02 1.8 2.1 (0.2) 0.3 0.01 sex life? 14. How satisfied have you been with your sexual 2.2 3.2 (0.2) 0.01 2.5 2.7 (0.2) 0.34 0.02 relationship? 15. How do you rate your confidence that you could 1.8 3.6 (0.2) 0.01 1.6 1.7 (0.2) 0.1 0.01 get and keep an erection? * Least squares mean (SE). † Baseline vs final scores. ‡ Overall treatment effect. 1070 BREMELANOTIDE FOR TREATMENT OF SILDENAFIL FAILURE vascular, neural and hemodynamic events, the end result of TABLE 5. Adverse effects which is cGMP mediated increased inflow of blood to the penis, a concomitant decrease of venous outflow and produc- No. Bremelanotide (%) No. Placebo (%) p Value tion of an erection.18 The central nervous system (CNS) and, more specifically, the structures and neurotransmitters Nauseain- 22 (12.8) 3 (1.8) 0.01 18 (10.5) 0 (0) 0.001 volved in the control of penile erection, are potentiallyDiaphoresis a 16 (9.3) 0 (0) 0.001 valuable alternative target for ED treatments. In theLow CNSback pain 12 (7) 0 (0) 0.001 melanocortins influence multiple physiological responses,Taste disturbances 8 (4.7) 0 (0) 0.001 Headache 6 (3.5) 4 (2.4) 0.07 including sexual behavior.Bremelanotide is a syntheticSomnolence 2 (1.2) 2 (1.2) 0.1 analog ␣of -melanocyte stimulating hormone. Insomnia 0 (0) 2 (1.2) 0.08 ␣ -Melanocyte stimulating hormone is one of several mela- nocortins that arise from posttranslational processing of a precursor peptide . Melanocortin an- alogs can enhance sexual function in human maleslocity (erec- 20 cm per second or less responded to bremelanotide. tile activity) and females (increased levels of sexualOf desirethe 342 patients 47 (13.7%) had diabetes mellitus and 238 and genital arousal).19 (69.6%) had 2 or more vascular risk factors in addition to Attempts at sildenafil salvage by urologists and primarydiabetes. Of 47 diabetic nonresponders to sildenafil 15 care physicians should be considered as the first step(31.9%) in EDresponded to bremelanotide. Improved erections treatment for initial failure. In this study 13% wereof nonre- reported by approximately 50% to 60% of patients with sponders were responder after reeducation. An attemptdiabetes at mellitus treated with sildenafil.20 sildenafil salvage with reeducation is necessary and usefulThe ideal treatment for pharmacotherapy of ED includes in all patients prior to declaring that treatment hasreliable actually efficacy, prompt onset of action, safe profile, and failed. Also, in sildenafil nonresponders, trying a sufficientsecond duration of action after a single dose. Oral admin- PDE-5 inhibitor or adjunct therapy is istrationworth- of bremelanotide is not possible since it would be while. According to our results, the main recognizedquickly reason degraded in the gastrointestinal tract. for sildenafil failure was lack of effect. In the previousThe phasesignificant incidence of sildenafil in nonresponder ED II studies bremelanotide induced significant erectilecases, re- its contraindication in patients taking organic ni- sponse i n mwith e nerectile dysfunction in healthy maletrates or␣ -blockers, and its side effects such as headache, subjects and in patients with an inadequate responseflushing to and changes in color vision is likely to increase in sildenafil.11,13 Our investigation showed the efficacy importanceof as the number of men beginning ED treatment bremelanotide treatment in a group of patients whoincreases were in the coming years. unresponsive to sildenafil. Bremelanotide was associated with a significant increase, with respect to baseline,CONCLUSIONS in the mean end of treatment scores for question 3 and 4 of the IIEF. Most adverse effects were mild and tolerable,To ourbut knowledge this is the first large scale, at-home study nausea can be bothersome for some patients. of intranasal bremelanotide. Bremelanotide can be used by While improvederectile function is the main goal individualsof ED who have not responded to sildenafil, who can- therapy, quality of life is also enhanced as subjectsnot toleratebe- the side effects of PDE-5 inhibitors and in whom come more satisfied with sexual activity. We also sildenafilused an is contraindicated. Future clinical trials will pro- inventory for analysis of satisfaction scores for thevide furthermen information about its safety, efficacy, optimal or their wives. Satisfaction scores significantly improveddoses and indications. Further studies to discover new tar- with bremelanotide. gets acting on alternative pathways controlling sexuality are Our study group comprised highly selected patientswarranted. with severe vasculogenic erectile dysfunction. Of the 49 patients with cavernous venous leakage and a flow to maintain rate of 30 ml per minute or greater 2 had score of 3 to both Abbreviations and Acronyms questions, whereas 29 of 42 with cavernous venous leakage ϭ and flow to maintain rate of less than 30 ml perED minute erectile dysfunction ϭ achieved this score. Only 2 patients with peak systolicIIEF ve- International Index of Erectile Function MC ϭ melanocortin PDE ϭ phosphodiesterase

TABLE 4. Sexual satisfaction scores Baseline Final p Value REFERENCES

Bremelanotide: 1. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ and Mean No. coitus/wk 1.2 2.2 0.03 McKinlay JB: Impotence and its medical and psychosocial Mean IIEF intercourse satisfaction11 16 0.03 correlates: results of the Massachusetts Male Aging Study. domain values Sexual satisfaction score 1.3 3.2 0.03 J Urol 1994;151: 54. Placebo: 2. www.viagramd.com/pi/proPackInsert.asp. Accessed Septem- Mean No. coitus/wk 1.3 1.4 Not significant ber 17, 2003. Mean IIEF intercourse satisfaction 11 10 Not significant 3. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD domain values Sexual satisfaction score 1.3 1.5 Not significant and Wicker PA: Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; ϭ NS Not significant 338: 1397. BREMELANOTIDE FOR TREATMENT OF SILDENAFIL FAILURE 1071

4. Salonia A, Rigatti P and Montorsi F: Sildenafil in erectile dys- pharmacokinetic properties and pharmacodynamic effects function: a critical review. Curr Med Res Opin 2003; 19: 241. of intranasal PT-141, a , in 5. Souverein PC, Egberts AC, Meuleman EJ, Urquhart J and healthy males and patients with mild-to-moderate erectile Leufkens HG: Incidence and determinants of sildenafil (dis) dysfunction. Int J Impot Res 2004; 16: 51. continuation: the Dutch cohort of sildenafil users. Int J Im- 13. Rosen RC, Diamond LE, Earle DC, Shadiack AM and Molinoff pot Res 2002; 14: 259. PB: Evaluation of the safety, and phar- 6. El-Galley R, Rutland H, Talic R, Keane T and Clark H: Long- macodynamic effects of subcutaneously administered PT- term efficacy of sildenafil and tachyphylaxis effect. J Urol 141, a melanocortin receptor agonist, in healthy male sub- 2001; 166: 927. jects and in patients with an inadequate response to 7. Giuliano F and Allard J: Apomorphine SL (Uprima): preclini- Viagra. Int J Impot Res 2004; 16: 135. cal and clinical experiences learned from the first central 14. NIH Consensus Conference: Impotence. NIH Consensus De- nervous system-acting ED drug. Int J Impot Res 2002; 14: velopment Panel on Impotence. JAMA 7;1993; 270: 83. S53. 15. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J and 8. Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ, Mishra A: The International Index of Erectile Function Dorr R et al: Synthetic melanotropic peptide initiates erec- (IIEF): a multidimensional scale for assessment of erectile tions in men with psychogenic erectile dysfunction: double dysfunction. Urology 1997; 49: 822. blind crossover placebo-controlled study. J Urol 1998; 160: 16. Kim SW and Paick JS: Short-term analysis of the effects of as 389. needed use of sertraline at 5 pm for the treatment of pre- 9. Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME and Levine N: Effect of an alpha melanocyte stimulating hor- mature ejaculation. Urology 1999; 54: 544. mone analog on penile erection and sexual desire in men 17. Fugl-Meyer AR, Lodnert G, Branholm IB and Fugl-Meyer KS: with organic erectile dysfunction. Urology 2000; 56: 641. On life satisfaction in male erectile dysfunction. Int J Impot 10. Molinoff PB, Shadiack AM, Earle D, Diamond LE and Quon Res 1997; 9: 141. CY: PT-141: a melanocortin agonist for the treatment of 18. Krane RJ, Goldstein I and Saenz De Tejada I: Impotence. sexual dysfunction. Ann N Y Acad Sci 2003; 994: 96. N Engl J Med 1989; 321: 1648. 11. Diamond LE, Earle DC, Garcia WD and Spana C: Co-admin- 19. Hadley ME: Discovery that a melanocortin regulates sexual istration of low doses of intranasal PT-141, a melanocortin functions in male and female humans. 2005; 26: receptor agonist, and sildenafil to men with erectile dys- 1687. function results in an enhanced erectile response. Urology 20. Safarinejad MR: Oral sildenafil in the treatment of erectile 2005; 65: 755. dysfunction in diabetic men: a randomized double-blind 12. Diamond LE, Earle DC, Rosen RC, Willett MS and Molinoff and placebo-controlled study. J Diabetes Complications PB: Double-blind, placebo-controlled evaluation of the safety, 2004; 18: 205.