International Journal of Impotence Research (2008) 20, S17–S23; doi:10.1038/ijir.2008.18

Clinical applications of centrally acting agents in male sexual dysfunction

W J G Hellstrom1

1Tulane University Medical Center, New Orleans, LA, USA

Correspondence: Dr WJG Hellstrom, Tulane University Medical Center, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112, USA. E-mail: [email protected]

Top

Abstract

Currently available agents for erectile dysfunction (ED) share the same mechanism of action and pharmacologic properties. Therefore, they share the same limitations, including a principal focus on erection as an end-organ process. One of the relatively unexplored areas of research has been the potential for centrally acting agents to improve male sexual response. A variety of neurohormones and neurotransmitter systems are involved in the male sexual response, including testosterone, dopamine, serotonin and the melanocortin systems. Investigations to determine the utility of centrally acting agents as monotherapy or adjunctive therapy in men with ED or other forms of sexual dysfunction are underway. Bremelanotide, a melanocortin agonist, has been tested in men with ED and may prove to be one of the first centrally acting agents to have clinical utility in male sexual dysfunction.

Keywords:

male sexual dysfunction, erectile dysfunction, treatment, bremelanotide

Top

Introduction

The effectiveness of phosphodiesterase-5 (PDE-5) inhibitors in treating erectile dysfunction (ED) caused by a wide range of etiologies has functionally created a new field of medicine.1 However, PDE-5 inhibitors are not universally effective.2Because the currently available agents share the same mechanism of action and pharmacologic properties, they also share the same shortcomings.

PDE-5 inhibitors, and other erectogens such as alprostadil, primarily treat one aspect of the male sexual experience: the ability to achieve and maintain an erection to sexual satisfaction. Other sexual dysfunctions, including reduced sexual desire or libido, have even fewer treatment options.

The shortcomings of PDE-5 inhibitors include potentially reduced pharmacodynamics with food and alcohol.3, 4, 5 Therefore, the effectiveness of specific PDE-5 inhibitors may be greatly reduced in sexual encounters that follow everyday social situations designed to promote sexual receptivity (for example, parties or meals where high-fat foods and/or alcohol are served). PDE-5 inhibitors also lack efficacy in certain patient populations and have potentially severe adverse effects due to interactions with organic nitrates and α-blockers.

Clearly, there is room in our armamentarium for additional agents with different mechanisms of action, as well as agents that have the potential to impact aspects of male sexuality other than the biomechanical aspects of erection. As we reach the upper limit of the effectiveness of vasculogenic erectogens, other pathways may provide further benefits.

One of the relatively unexplored territories in male sexual dysfunction is the role of the central nervous system (CNS) on peripheral sexual function and the potential for centrally acting agents to improve sexual response6 (Figure 1). Preclinical models have advanced our understanding of neurotransmission, impulse propagation and intracellular transduction of neural signals to induce erection. On the basis of this research, a number of agents that appear to act at least partly via a central mechanism of action have been developed. Whether these agents might be directly erectogenic or have an impact on other aspects of sexuality, including libido, remains to be fully elucidated.

Figure 1.

Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorHypothalamic control of penile erection and sexual behavior is modulated by a variety of biochemical pathways. Dopamine appears to be the primary erectogenic neurotransmitter, and serotonin acts as an inhibitor. Excitatory amino acids involved in sexual function include NDMA (N-methyl-d-aspartate, l-aspartate); GABA (gamma aminobutyric acid); GHRP (growth hormone-releasing peptide); NA (noradrenalin (α1-AR produces stimulation; α1-AR inhibits sexual behavior)); and NO (nitric oxide)6 (with permission from Elsevier).

Full figure and legend (17K)

Top

Neurohormones and male sexual function

A good deal of attention has been paid to hypogonadism and the effects of testosterone replacement on sexual function in hypogonadal or even eugonadal men.7, 8, 9, 10, 11, 12, 13, 14 In the brain, steroids focus attention toward sexual stimuli and identify them as sexual in nature.15 Testosterone has a variety of effects systemically and as a neurohormone; because of its wide-ranging impact on multiple body systems, its role in facilitating the sexual response may be underappreciated.

In hypogonadal men, testosterone replacement therapy improves libido as well as ED.9 This argues, at least in part, for a CNS mechanism of action of testosterone. In addition, nocturnal penile tumescence is impaired in hypogonadal men, but is restored in men who undergo testosterone replacement therapy.14 However, there is limited evidence that testosterone replacement enhances sexual desire in eugonadal men with a low sexual desire disorder. One small placebo-controlled crossover study found a statistically significant improvement in sexual interest, but not in erectile function (EF); however, results from the study have not yet been reproduced.16 Furthermore, in a study of hypogonadal men complaining of sexual disorders of non-organic origin, testosterone replacement therapy failed to improve sexual interest.17

A meta-analysis of 17 randomized, placebo-controlled studies of testosterone replacement therapy for sexual dysfunction found that testosterone improved EF, but not libido, and was inversely related to the mean baseline testosterone concentration.18 In addition, benefits from testosterone tended to decline over time. The authors conclude that the level of testosterone needed in the CNS to maintain sexual arousability is probably lower than that needed in the periphery. In the older male, the situation is complicated by increased binding of free testosterone via sex steroid–binding hormones, as well as other age-related effects on the hypothalamic–pituitary axis.

Top

Dopaminergic agents

Dopamine appears to be the primary pro-erectile CNS neurotransmitter. Parkinson’s disease patients treated with dopaminergic substances such as apomorphine, levodopa or bromocriptine report the occurrence of erections and increased libido or an improved sexual interest.

In a study of human volunteers, a single dose of levodopa facilitated somatic motor responses in response to sexual stimuli among men, but not women.19 In these volunteers, levodopa was administered with carbidopa in order to prevent its metabolism in the periphery. The subjects were asked to fantasize erotically for 2min, after which they were shown an erotic film for 6min. Subjects completed a questionnaire about their sexual activity in the 24h after dosing. Male subjects had higher postexperimental sexual desire scores on follow-up and had higher levels of sexual activity compared with placebo.

Apomorphine is a dopamine agonist that has been tested as a CNS-acting treatment for ED.20, 21, 22, 23 It is degraded by the first-pass metabolism, so must be taken via injection, sublingually, or via a nasal spray formulation. The drug is not approved in the United States for an ED indication, but is available in the European Union.24

One of the largest clinical trials of apomorphine was a double-blind, dose-escalation study.23 A total of 569 patients were randomized to four groups: (1) a dose-optimization group in which patients began with 2mg, increased or decreased the dosage as needed for 4 weeks, and thereafter maintained an optimal dose for 4 weeks; (2) a fixed-dose group of 5mg; (3) a fixed-dose group of 6mg; and (4) a placebo group. A statistically significantly higher percentage of patients receiving apomorphine reported achieving and maintaining erections firm enough for intercourse versus the placebo group (48–53% vs 35% for placebo, Pless than or equal to0.001). In addition, a significantly higher percentage of attempts in the apomorphine group resulted in intercourse (45–51% vs 33%, Pless than or equal to0.001).

Several clinical trials have tested apomorphine against sildenafil.25, 26, 27, 28These studies have consistently shown that sildenafil is more effective than apomorphine in men with ED, and particularly among those with ED of vasculogenic origins. In addition, up to 96% of men in these studies who tried both compounds preferred sildenafil. Nausea, which appears to be the dose-limiting adverse event of apomorphine, is dose-related and may subside with continued treatment. Tests of the nasal spray formulation are being conducted in order to determine if this method of administration reduces the adverse events. Although the compound was approved for use by European regulatory authorities in 2001, the sponsor did not seek renewal of that authorization, which then expired in 2006.

Top

Adrenergic blockade

Yohimbine is a ‘nutraceutical’ that has been proposed as a ‘natural’ treatment for ED for several decades. Yohimbine is thought to facilitate sexual arousal by acting on α2-adrenoceptors in the CNS and by blockade of adrenergic-mediated detumescence.29 A meta-analysis of clinical trials conducted using yohimbine as a treatment for ED found it to be superior to placebo (odds ratio 3.85).30 Data regarding other adrenergic agents such as phentolamine, doxazosin and prazosin are limited, and the putative mechanism of action of these agents on ED appears to be peripheral, not central, in nature.29

Top

Serotonin

In the periphery, serotonin may have a role in maintaining penile detumescence and flaccidity in the absence of sexual signals.31 Sexual functioning is diminished by selective serotonin reuptake inhibitors (SSRIs) used as antidepressants.32 The mechanism of action for SSRI-induced sexual dysfunction appears to be related to the impact of serotonin on dopamine transport, decrease in dopamine transmission, and more efficient removal of dopamine from the synaptic regions.33, 34 In addition to reduced desire for sexual activity, increased serotonin levels may cause retrograde or delayed ejaculation, the determination of which resulted in the use of SSRIs to treat premature ejaculation.35

Bupropion, which is not an SSRI, does not appear to have the same sexual side effects as other modern antidepressants.36, 37, 38 Although bupropion may reverse SSRI-induced sexual dysfunction, it is still unclear whether bupropion is useful in treating sexual dysfunctions caused by other etiologies.39, 40, 41However, the fact that antidepressant-related sexual dysfunction can be managed pharmacologically indicates the importance of CNS-acting neurotransmitters in the sexual cycle.42

Top

Other CNS targets

A number of other CNS targets have been proposed for their impact on sexual function.6 These targets, including NDMA, GABA, growth-hormone releasing peptides, oxytocin and even NO itself, have yet to report substantial results in humans.

Top

Melanocortins

The melanocortin family of neuropeptides is derived from the polypeptide precursor proopiomelanocortin, and includes β-endorphin, ACTH and α-MSH.43The melanocortin 4 receptor, implicated in the control of food intake and energy expenditure, also modulates EF and sexual behavior.44 As reviewed in this supplement by Shadiack and Althof, these peptides have pronounced effects on the sexual behavior on mice, rats and nonhuman primates.

Bremelanotide is under commercial development for the treatment of both male and female sexual dysfunction, including ED and female sexual arousal disorder, respectively. Several early clinical trials have been reported on the efficacy and safety of bremelanotide in males with ED, both as monotherapy and in combination with sildenafil.45, 46, 47

Two Phase 1 safety studies of bremelanotide have been conducted in healthy volunteers.45, 46 One study provided bremenalotide subcutaneously, whereas the second used the intranasal formulation that has been chosen for further clinical development. In both evaluations, erectile response was measured using the RigiScan device, without providing participants with additional sexual stimulation such as erotic videos. Both studies showed that bremelanotide was safe and erectogenic at reasonable doses (above 7mg for the intranasal formulation).

Intranasal bremelanotide was found to be erectogenic in a Phase 2a study conducted among 25 men with moderate to severe ED who reported an inadequate response to sildenafil monotherapy.45 To be eligible for this study, men had to report a less than 50% success rate in achieving an erection suitable for vaginal penetration while taking 100mg sildenafil. The study was conducted in a three-way crossover design where all subjects received subcutaneous 4mg bremelanotide, 6mg bremelanotide or matching placebo during the course of the trial. Although the study was blinded, due to safety considerations, the subjects were assigned to treatment in such a manner so that they always received the 4mg bremelanotide dose before receiving the 6mg dose.

Subjects were monitored for safety for 24h. RigiScan monitoring was conducted over a total of 145min of observation beginning 30min after dosing. During that monitoring, erotic videos were shown to the subjects during two separate 30-min sessions. This study with bremelanotide resulted in a clinically and statistically significant erectile response in the presence of visual sexual stimuli compared with placebo. Mean durations of greater than or equal to60% base rigidity with the RigiScan device were 28 and 41min for subjects receiving the 4 and 6mg bremelanotide, respectively, compared to 6min for patients receiving placebo (Figure 2). Among the 10 patients in this group who had severe ED at baseline, the duration of greater than or equal to60% base rigidity with 6mg bremelanotide was 36min versus 8min with placebo (P<0.01).

Figure 2.

Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorDuration of base rigidity greater than or equal to60 or greater than or equal to80% by Rigiscan after subcutaneous administration of bremelanotide among men with ED and an inadequate response to sildenafil (N=25). ***P<0.001, compared with placebo.45 ED, erectile dysfunction. Reprinted with permission from Macmillan Publishers Ltd: International Journal of Impotence Research (Rosen et al.45), copyright (2004).

Full figure and legend (13K)

 

A second Phase 2a study confirmed the erectogenic properties of the nasal spray formulation of bremelanotide among 24 subjects with mild to moderate ED.46 In this evaluation, men with ED had been successfully treated with sildenafil within the previous 6 months and were current users of sildenafil. Following a single intranasal dose of 4, 7, 10 or 20mg of bremelanotide or matching placebo, subjects were monitored by RigiScan monitoring over a total of 145min, beginning 30min after dosing. Erotic visual stimulation was provided during two 30-min segments. At doses above 7mg, bremelanotide was erectogenic, based on RigiScan measurements of the duration of base and tip penile rigidity greater than or equal to60%, as well as penile base and tip rigidity and tumescence (Figure 3).

Figure 3.

Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorMean (s.e.) duration of base rigidity greater than or equal to60 and greater than or equal to80% following single-dose administration of bremelanotide in ED patients responsive to sildenafil. Duration of base rigidity during a 2.5h RigiScan monitoring session with two 30-min sessions of visual sexual stimulation in ED patients treated with placebo, 7 and 20mg of bremelanotide (N=24).**P<0.01; ***P<0.001.46 ED, erectile dysfunction. Reprinted with permission from Macmillan Publishers Ltd: International Journal of Impotence Research (Diamond LE et al.46), copyright (2004).

Full figure and legend (14K)

 

Additionally, a study of combination therapy with bremelanotide and low-dose sildenafil was undertaken among 19 patients who were previous responders to either sildenafil or vardenafil therapy for ED.47 Comorbidities of this population included smoking, obesity, diabetes mellitus, hypertension and hyperlipidemia. In this randomized, crossover study design, patients were provided with a single dose of 25mg sildenafil and 7.5mg intranasal bremelanotide, 25mg sildenafil and an intranasal placebo spray, or a placebo tablet and an intranasal placebo spray. Two 30-min episodes of visual sexual stimulation were provided during a 2.5-h postdose period where erectile response was assessed by RigiScan. Co-administration of bremelanotide and low-dose sildenafil resulted in a significantly greater erectile response compared with low-dose sildenafil alone (Figure 4). When co-administered with 25mg sildenafil, no new adverse events were reported, nor was there an increase in severity of adverse events associated with either sildenafil or bremelanotide therapy. The co-administration of sildenafil and bremelanotide may offer a potential for dose reduction of both treatments, potentially improving the adverse event profile while maintaining good efficacy outcomes.

Figure 4.

Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorRigiScan monitoring results for bremelanotide+sildenafil versus sildenafil alone and placebo. Time of base rigidity greater than or equal to60% during a 2.5-h RigiScan monitoring session (30min to 3h postdose).47

Full figure and legend (15K)

 

Two larger Phase 2b clinical trials of bremelanotide have been completed in men with ED. The first 12-week randomized, placebo-controlled trial was among 726 nondiabetic men with ED.48 Participants were randomized to receive placebo or one of five doses of bremelanotide intranasally (5, 7.5, 10, 12.5 or 15mg). After receiving the study medication, they were instructed to attempt sexual intercourse at least twice a week for the first month. The primary study end point was the change in the EF domain of the IIEF (International Index of Erectile Function). At the end of the 12-week study period, EF domain scores of all participants receiving bremelanotide above 5mg showed a statistically significant improvement over placebo (Figure 5). Secondary end points, including questions 2 and 3 of the SEP (Sexual Encounter Profile) dealing with the ability to penetrate and maintain erection to completion, also showed significant improvements with bremelanotide doses above 5mg.

Figure 5.

Figure 5 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorMean change in IIEF-EF domain scores from baseline after 12 weeks of therapy with bremelanotide or placebo. LOCF-ITT population. Bremelanotide doses above 5mg were associated with statistically significant increases in EF domain scores compared with placebo.48 IIEF, International Index of Erectile Function; EF, erectile function.

Full figure and legend (22K)

 

In a separate quality of life analysis, changes between baseline and 12-week outcomes in the Self-Esteem and Relationship (SEAR) questionnaire were reported.49 At the end of the 12-week study, patients reported statistically significant improvements in all SEAR domains. Qualitatively, this indicates that the sexual experience of men taking bremelanotide was superior to that without, and subjects reported that bremelanotide both restored EF and improved their confidence and self-esteem. Additional data regarding the qualitative experience of men undergoing bremelanotide treatment are forthcoming.

The second Phase 2b clinical trial was conducted among 294 adult males with ED and a diagnosis of controlled type I or type II diabetes mellitus.50 Subjects were randomized into groups of placebo, 10, 12.5 or 15mg bremelanotide, given intranasally. Subjects received one in-clinic dose of study medication before 12 weeks of at-home treatment. The primary efficacy outcome was the change in IIEF-EF domain score from baseline to week 12. Data from this population showed an increase in EF domain scores for the two higher doses of bremelanotide compared with placebo.

Because bremelanotide appears to be centrally acting, it opens up the possibility for its use in women with various forms of sexual dysfunction. In a study of 18 premenopausal women with a primary diagnosis of female sexual arousal disorder, a single dose of bremelanotide significantly improved subjects’ 24-h self-reporting of sexual activity.51 A similar study has been completed in a group of postmenopausal women with female sexual arousal disorder, and results should be reported shortly. In addition, an ongoing at-home study of bremelanotide has enrolled 300 pre- and post-menopausal female sexual arousal disorder subjects from approximately 20 clinical sites throughout the United States.

Adverse events accumulated primarily in a dose-dependent manner, with transient nausea most frequently reported at a range of 15% for lower doses to 35% for higher doses. It appears that the risk of nausea is most evident after the first dose; subsequent doses have lower risk of nausea. Other commonly seen adverse events include flushing (21–25%), headache (7–14%), vomiting (<1–15%) and transient (1–3h post single dose) increases in systolic blood pressure (7–17%). Most adverse events were mild to moderate in severity.

Top

Discussion

The ongoing evaluation of centrally acting agents for male sexual dysfunction may become clinically important as we reach the efficacy limits of the currently available agents. Finding additional biological pathways of sexual response leads to alternative treatments that can be used when the current gold standard therapy of PDE-5 inhibitors is either ineffective or not well tolerated. Future research will determine whether agents utilizing these alternative pathways result in better clinical outcomes for a majority of patients or for those with certain specific sexual dysfunction diagnoses.

Agents that work on alternative biological pathways may also provide opportunities to augment the responses seen with peripherally acting erectogens. Whether combination therapy will allow improved responses to those who have been dissatisfied with currently available therapies, or whether combination therapy will be used to provide greater therapeutic benefit with fewer adverse events (for example, via dose-reduction strategies) is a fertile field for future research.

Top

Notes

Disclosure

Dr Hellstrom serves as a consultant/advisor, lecturer and/or clinical trial investigator for the following: VIVUS, Mentor, Bayer, Pfizer, Johnson & Johnson, Auxilium, King, Palatin, American Medical Systems, Medtronic, GlaxoSmithKline, Coloplast and Sanofi-Synthelabo.

Top

References

  1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA et al. Oral sildenafil in the treatment of erectile dysfunction. N Eng J Med1998; 338: 1397–1404. | Article | ISI | ChemPort |
  2. Raina R, Lakin ML, Agarwal A, Sharma R, Goyal KK, Montague DK et al. Long-term effect of sildenafil citrate on erectile dysfunction after radical prostatectomy: 3-year follow-up. Urology 2003; 62: 110–115. | Article | PubMed | ISI |
  3. Viagra [ package insert] . Pfizer Labs: New York NY, 2006.
  4. Levitra [ package insert] . Bayer Pharmaceuticals Corporation: West Haven CT, 2007.
  5. Cialis [ package insert] . Lilly ICOS LLC: Indianapolis IN, 2003.
  6. Kendirci M, Walls MM, Hellstrom WJ. Central nervous system agents in the treatment of erectile dysfunction. Urol Clin N Am 2005; 32: 487–501. | Article |
  7. Ojumu A, Dobs AS. Is hypogonadism a risk factor for sexual dysfunction? J Androl 2003; 24: S46–S51. | PubMed |
  8. Carani C, Bancroft J, Del Rio G, Granata AR, Facchinetti F, Marrama P. The endocrine effects of visual erotic stimuli in normal men.Psychoneuroendocrinology 1990; 15: 207–216. | Article | PubMed | ChemPort |
  9. Seftel A. Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents. Int J Impot Res 2007; 19: 2–24. | Article | PubMed | ChemPort |
  10. Schubert M, Jockenhovel F. Late-onset hypogonadism in the aging male (LOH): definition, diagnostic and clinical aspects. J Endocrinol Invest 2005;28(3 Suppl): 23–27. | PubMed | ISI | ChemPort |
  11. Rhoden EL, Morgataler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350: 482–492. | Article | PubMed | ISI | ChemPort |
  12. Haren MT, Kim MJ, Tariq SH, Wittert GA, Morley JE. Andropause: a quality-of-life issue in older males. Med Clin North Am 2006; 90: 1005–1023. | Article | PubMed | ChemPort |
  13. Lazarou S, Morgentaler A. Hypogonadism in the man with erectile dysfunction: what to look for and when to treat. Curr Urol Rep 2005; 6: 476–481. | Article | PubMed |
  14. Bancroft J. The endocrinology of sexual arousal. J Endocrin 2005; 186: 411–427. | Article | ChemPort |
  15. Scepkowski LA, Georgescu M, Pfaus JG. Neuroendocrine factors in sexual desire and motivation. In: Goldstein I, Traish A, Davis S, Meston C (eds).Women’s Sexual Function and Dysfunction. Taylor & Francis Ltd: London, 2005, pp 159–168.
  16. O’Carroll R, Bancroft J. Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry 1984; 145: 146–151. | PubMed | ChemPort |
  17. Frajese G, Lazzari R, Magnani A, Moretti C, Sforza V, Nerozzi D. Neurotransmitter, opiodergic system, steroid-hormone interaction and involvement in the replacement therapy of sexual disorders. J Steroid Biochem Mol Biol 1990; 37: 411–419. | Article | PubMed | ChemPort |
  18. Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxford) 2005; 63: 381–394. | Article | ChemPort |
  19. Both S, Everaerd W, Laan E, Gooren L. Effect of a single dose of levodopa on sexual response in men and women. Neuropsychopharmacology 2005;30: 173–183. | Article | PubMed | ChemPort |
  20. Lal S, Ackman D, Thavundayil JX, Kiely ME, Etienne P. Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry 1984; 8: 695–699. | Article | PubMed | ChemPort |
  21. Heaton JP, Morales A, Adams MA, Johnston B, el-Rashidy R. Recovery of erectile function by the oral administration of apomorphine. Urology 1995;45: 200–206. | Article | PubMed | ChemPort |
  22. Mirone VG, Stief CG. Efficacy of apomorphine SL in erectile dysfunction.BJU Int 2001; 88(s3): 25–29. | Article | PubMed | ChemPort |
  23. Dula E, Bukofzer S, Perdok R, George M, the Apomorphine SL Study Group. Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol 2001;39: 558–564. | Article | PubMed | ISI | ChemPort |
  24. Broderick GA. Oral pharmacotherapy and the contemporary evaluation and management of erectile dysfunction. Rev Urol 2003; 5(Suppl 7): S9–S20. | PubMed |
  25. Perimenis P, Markou S, Gyftopoulos K, Giannitsas K, Athanasopoulos A, Liatsikos E et al. Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study.Andrologia 2004; 36: 106–110. | Article | PubMed | ChemPort |
  26. Perimenis P, Gyftopoulos K, Giannitsas K, Markou SA, Tsota I, Chrysanthopoulou A et al. A comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in men with evidence of arteriogenic erectile dysfunction. Int J Impot Res 2004; 16: 2–7. | Article | PubMed | ChemPort |
  27. Eardley I, Wright P, MacDonagh R, Hole J, Edwards A. An open-label, randomized, flexible-dose, crossover study to assess the comparative efficacy and safety of sildenafil citrate and apomorphine in men with erectile dysfunction. Andrology 2004; 93: 1271–1275. | ChemPort |
  28. Porst H, Bebre HM, Jungwirth A, Burkart M. Comparative trial of treatment satisfaction, efficacy, and tolerability of sildenafil versus apomorphine in erectile dysfunction. An open, randomized cross-over study with flexible dosing. Eur J Med Res 2007; 12: 61–67. | PubMed | ChemPort |
  29. Maggi I, Filippi S, Ledda F, Magini A, Forti G. Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. Eur J Endocrinol2000; 143: 143–154. | Article | PubMed | ISI | ChemPort |
  30. Ernst E, Pittler MH. Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials. J Urol 1998; 159: 433–436. | Article | PubMed | ChemPort |
  31. Uckert S, Fuhlenriede MH, Becker AJ, Stief CG, Scheller F, Knapp WH et al. Is serotonin significant for the control of penile flaccidity and detumescence in the human male? Urol Res 2003; 31: 55–60. | PubMed | ISI |
  32. Clayton AH, Pradko JF, Croft HA, Montano CB, Leadbetter RA, Bolden-Watson C et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002; 63: 357–366. | PubMed |
  33. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999; 19: 67–85. | Article | PubMed | ISI | ChemPort |
  34. Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison RT, Baldwin RM et al. Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration.Neuropsychopharmacology 2003; 28: 413–420. | Article | PubMed | ISI | ChemPort |
  35. Waldinger MD. The neurobiological approach to premature ejaculation. J Urol 2002; 168: 2359–2367. | Article | PubMed | ISI |
  36. Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A et al. ‘Dopamine-dependent’ side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry 2004; 65: 1064–1068. | PubMed | ChemPort |
  37. Zisook S, Rush AJ, Haight BR, Clines DC, Rockett CB. Use of bupropion in combination with serotonin reuptake inhibitors. Biol Psychiatry 2006; 59: 203–210. | Article | PubMed | ChemPort |
  38. Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord 2006; 9: 27–32. | Article |
  39. Masand PS, Ashton AK, Gupta S, Frank B. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry 2001; 158: 805–807. | Article | PubMed | ChemPort |
  40. Clayton AH, Croft HA, Horrigan JP, Wightman DS, Krishen A, Richard NE et al. Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry 2006; 67: 736–746. | PubMed | ChemPort |
  41. DeBattista C, Solvason B, Poirier J, Kendrick E, Loraas E. A placebo-controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction. J Clin Psychiatry 2005; 66: 844–848. | PubMed | ChemPort |
  42. Taylor MJ. Strategies for managing antidepressant-induced sexual dysfunction: a review. Curr Psychiatry Rep 2006; 8: 431–436. | Article | PubMed |
  43. Voisey J, Carroll L, van Daal A. Melanocortins and their receptors and antagonists. Curr Drug Targets 2003; 4: 586–597. | Article | PubMed | ChemPort |
  44. Van der Ploeg LH, Martin WJ, Howard AD, Nargund RP, Austin CP, Guan Xet al. A role for the melanocortin 4 receptor in sexual function. Proc Nat Acad Sci 2002; 99: 11381–11386. | Article | PubMed | ChemPort |
  45. Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res 2004; 16: 135–142. | Article | PubMed | ISI | ChemPort |
  46. Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res 2004; 16: 51–59. | Article | PubMed | ISI | ChemPort |
  47. Diamond LE, Earle DC, Garcia WD, Spana C. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response.Urology 2005; 65: 755–759. | Article | PubMed | ChemPort |
  48. Kaminetsky J, Zinner N, Gittleman M, Auerbach S, Fischkoff S. Phase IIb study of bremelanotide in the treatment of ED in non-diabetic males.Proceedings of the American Urology Association Annual Meeting; 19–24 May 2007; Anaheim, USA.
  49. Althof SE, Pereman MA, Rosen RC, Fischkoff S, Earle D. Improvement in sexual relationship satisfaction, confidence, and self-esteem in erectile dysfunction patients treated with bremelanotide. Proceedings of the American Urology Association Annual Meeting; 19–24 May 2007; Anaheim, USA.
  50. Hellstrom WJ, Gittelman M, Zinner N, Hallam T, Harning R, Dworaczyk DAet al. Randomized, double-blind, placebo-controlled, at-home study to evaluate the efficacy and safety of intranasal bremelanotide in men with erectile dysfunction with and without diabetes mellitus. Proceedings of the European Society for Sexual Medicine (ESSM) Annual Meeting; 3–6 December 2006; Vienna, Austria.
  51. Diamond LE, Earle DC, Heiman JC, Rosen RC, Perelman MA, Harning R. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med 2006; 3: 628–638. | Article | PubMed | ChemPort |
Top

Acknowledgements

This work was supported by a grant from Palatin Technologies, Inc. Editorial support for the development of this paper was provided by Kevin Kehres.