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An update on new oral PDE5 inhibitors for the treatment of erectile dysfunction

Nature Reviews Urology volume 7, pages 603–609 (2010)Cite this article

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Abstract

The management of erectile dysfunction (ED) has been revolutionized by the discovery of phosphodiesterase 5 (PDE5) inhibitors, which have been commercially available for more than a decade and are the first-line therapeutic option for men with ED. Sildenafil, vardenafil and tadalafil were approved by the European Medicine Agency and the US FDA for the treatment of ED on the back of their high efficacy rates and favorable safety profiles. However, despite the fact that more than 50 million patients with ED worldwide have been successfully treated with one of these PDE5 inhibitors, some men—most notably those with severe neurologic damage, diabetes mellitus or severe vascular disease—are resistant to the currently available drugs and require more-invasive treatments, such as intracavernosal injection therapy. Partly as a consequence of this, research into alternative therapeutic approaches continues, including the development of new PDE5 inhibitors, centrally acting pharmaceutical agents, and application of molecular technologies such as gene therapy and stem cell therapy.

Key Points

  • Phosphodiesterase type 5 (PDE5) inhibitors remain the first-line therapy for most men with erectile dysfunction (ED)

  • The currently available PDE5 inhibitors (sildenafil, vardenafil and tadalafil) are all highly effective and well tolerated

  • New PDE5 inhibitors under clinical development differ from established agents mainly in terms of their pharmacokinetics, and possibly in relation to their selectivity

  • Other approaches to the treatment of ED include the use of centrally acting agents, gene therapy and stem cell therapy; such approaches are currently some way away from everyday clinical practice

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Figure 1: Mechanism of action of PDE5 inhibitors.

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References

  1. Corbin, J. D. & Francis, S. H. Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem. 274, 13729–13732 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Corbin, J. D. & Francis, S. H. Pharmacology of phosphodiesterase-5 inhibitors. Int. J. Clin. Pract. 56, 453–459 (2002).

    CAS  PubMed  Google Scholar 

  3. Eardley, I. et al. Pharmacotherapy for erectile dysfunction. J. Sex. Med. 7 (1 Pt 2), 524–540 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Porst, H. et al. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 62, 121–125 (2003).

    Article  PubMed  Google Scholar 

  5. Kim, B. H. et al. Safety, tolerability, and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects. Br. J. Clin. Pharmacol. 65, 848–854 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Prince, W. et al. SLx-2102, a new long-acting PDE5 inhibitor: preliminary safety, tolerability, PK and endothelial function effects in healthy subjects. J. Urol. 175 (Suppl. 4), 924 (2006).

    Google Scholar 

  7. Moncada, I., Jara, J., Subirá, D., Castaño, I. & Hernández, C. Efficacy of sildenafil citrate at 12 hours after dosing: re-exploring the therapeutic window. Eur. Urol. 46, 357–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Porst, H. et al. Evaluation of the efficacy and safety of once-a-day dosing of tadalafil 5 mg and 10 mg in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. Eur. Urol. 50, 351–359 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Rajfer, J. et al. Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double blind, placebo-controlled study in the US. Int. J. Impot. Res. 19, 95–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Porst, H. et al. Long-term safety and efficacy of tadalafil 5 mg dosed once daily in men with erectile dysfunction. J. Sex. Med. 5, 2160–2169 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Eardley, I. et al. An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naive to phosphodiesterase 5 inhibitor therapy. BJU Int. 96, 1323–1332 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Tolrà, J. R., Campaña, J. M., Ciutat, L. F. & Miranda, E. F. Prospective, randomized, open-label, fixed-dose, crossover study to establish preference of patients with erectile dysfunction after taking the three PDE-5 inhibitors. J. Sex. Med. 3, 901–909 (2006).

    Article  PubMed  Google Scholar 

  13. Rubio-Aurioles, E. et al. Comparing vardenafil and sildenafil in the treatment of men with erectile dysfunction and risk factors for cardiovascular disease: a randomized, double-blind, pooled crossover study. J. Sex. Med. 3, 1037–1049 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Doh, H. et al. Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. Arch. Pharm. Res. 25, 873–878 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Paick, J. S. et al. The efficacy and safety of udenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction. J. Sex. Med. 5, 946–953 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Park, N. C., Min, K. S. & Paick, J. S. Efficacy of udenafil for the treatment of erectile dysfunction up to 12 hours after dosing: a randomized controlled trial [abstract PS-02-013]. J. Sex. Med. 3 (Suppl. 3), 180 (2006).

    Google Scholar 

  17. Kim, J. J. Efficacy and safety of fixed-dose Udenafil (Zydena®) in men with diabetes and erectile dysfunction [abstract P-06-056]. J. Sex. Med. 5 (Suppl. 2), 63 (2008).

    Google Scholar 

  18. Kangwon, K. et al. The efficacy and safety of once-a-day dosing of udenafil in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study [abstract PD-056]. J. Sex. Med. 6 (Suppl. 2), 65 (2009).

    Google Scholar 

  19. Lee, H. S. et al. Identification of cytochrome P450 enzymes responsible for N-dealkylation of a new oral erectogenic, mirodenafil. Xenobiotica 38, 21–33 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Paick, J. S. et al. Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction. J. Sex. Med. 5, 2672–2680 (2008).

    Article  PubMed  Google Scholar 

  21. Park, N. C. et al. Efficacy and safety of oral mirodenafil in the treatment of erectile dysfunction in men with diabetes: a multi-center, randomized, double blind, placebo-controlled, fixed dose, parallel group clinical trial [abstract 370]. Eur. Urol. Suppl. 8, 213 (2009).

    Article  Google Scholar 

  22. Toque, H. A. et al. Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. Eur. J. Pharmacol. 591, 189–195 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Glina, S. et al. Efficacy and tolerability of lodenafil carbonate for oral therapy in erectile dysfunction: a phase II clinical trial. J. Sex. Med. 6, 553–557 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Kaufman, J. & Dietrich, J. Safety and efficacy of avanafil, a new PDE5 inhibitor for treating erectile dysfunction [abstract 923]. J. Urol. 175 (Suppl. 4), 299 (2006).

    Article  Google Scholar 

  25. Sweetnam, P. et al. SLx-2101, a novel long-acting phosphodiesterase-5 (PDE5) inhibitor for erectile dysfunction: in vivo and in vitro studies [abstract 51]. J. Sex. Med. 3 (Suppl. 1), 30 (2006).

    Google Scholar 

  26. Donabedian, D. et al. SLx-2101, a new long-acting PDE5 inhibitor: preliminary safety, tolerability, PK and endothelial function effects in healthy subjects [abstract MP-03-102]. J. Sex. Med. 3 (Suppl. 3), 209 (2006).

    Google Scholar 

  27. Van der Ploeg, L. H. et al. A role for the melanocortin 4 receptor in sexual function. Proc. Natl Acad. Sci. USA 99, 11381–11386 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rosen, R. C., Diamond, L. E., Earle, D. C., Shadiack, A. M. & Molinoff, P. B. 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. 16, 135–142 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Kaminetsky, J. et al. Phase IIB study of bremelanotide in the treatment of ED in non-diabetic males [abstract 1042]. J. Urol. 177 (4 Suppl.), 345 (2007).

    Article  Google Scholar 

  30. Steidle, C. P. et al. Phase IIB study of bremelanotide in the treatment of ED in diabetic males [abstract 1177]. J. Urol. 177 (4 Suppl.), 388 (2007).

    Article  Google Scholar 

  31. Christ, G. J. & Melman, A. The application of gene therapy to the treatment of erectile dysfunction. Int. J. Impot. Res. 10, 111–112 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Kendirci, M., Teloken, P. E., Champion, H. C., Hellstrom, W. J. & Bivalacqua, T. J. Gene therapy for erectile dysfunction: fact or fiction? Eur. Urol. 50, 1208–1222 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Melman, A., Bar-Chama, N., McCullough, A., Davies, K. & Christ, G. Plasmid based gene transfer for treatment of erectile dysfunction and overactive bladder: results of a phase I trial. Isr. Med. Assoc. J. 9, 143–146 (2007).

    CAS  PubMed  Google Scholar 

  34. Melman, A., Bar-Chama, N., McCullough, A., Davies, K. & Christ, G. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum. Gene Ther. 17, 1165–1176 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Gholami, S. S. et al. The effect of vascular endothelial growth factor and adeno-associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia. J. Urol. 169, 1577–1581 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Rogers, R. S., Graziottin, T. M., Lin, C. S., Kan, Y. W. & Lue, T. F. Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int. J. Impot. Res. 15, 26–37 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Liu, W. J. et al. Effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats. Asian J. Androl. 7, 381–388 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Eng, W. et al. Superoxide dismutase—a target for gene therapeutic approach to reduce oxidative stress in erectile dysfunction. Methods Mol. 610, 213–227 (2010).

    Article  Google Scholar 

  39. Azadzoi, K. M., Golabek, T., Radisavljevic, Z. M., Yalla, S. V. & Siroky, M. B. Oxidative stress and neurodegeneration in penile ischaemia. BJU Int. 105, 404–410 (2009).

    Article  PubMed  Google Scholar 

  40. Shen, Z. J. et al. Gene transfer of vasoactive intestinal polypeptide into the penis improves erectile response in the diabetic rat. BJU Int. 95, 890–894 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Bivalacqua, T. J., Champion, H. C., Abdel-Mageed, A. B., Kadowitz, P. J. & Hellstrom, W. J. Gene transfer of prepro-calcitonin gene-related peptide restores erectile function in the aged rat. Biol. Reprod. 65, 1371–1377 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Gonzalez-Cadavid, N. F. & Rajfer, J. Molecular pathophysiology and gene therapy of aging-related erectile dysfunction. Exp. Gerontol. 39, 1705–1712 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Bivalacqua, T. J. et al. Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction. Am. J. Physiol. Heart Circ. Physiol. 292, H1278–H1290 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Nolazco, G. et al. Effect of muscle-derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat. BJU Int. 101, 1156–1164 (2008).

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. University Hospital of North Tees, Hardwick Road, Stockton-on-Tees, Cleveland, TS19 8PE, UK

    Victor Palit

  2. Pyrah Department of Urology, St James University Hospital, Beckett Street, Leeds, LS9 7TF, West Yorkshire, UK

    Ian Eardley

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Both authors contributed equally to researching data for the article, discussing the content, writing, and review/editing of the manuscript before submission.

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Correspondence to Ian Eardley.

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Competing interests

I. Eardley has acted as a consultant for Eli Lilly and Company and Bayer Schering Pharma, and has received speakers' bureau (honoraria) and grant-research support from Pfizer, Eli Lilly and Company and Bayer Schering Pharma. V. Palit declares no competing interests.

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Palit, V., Eardley, I. An update on new oral PDE5 inhibitors for the treatment of erectile dysfunction. Nat Rev Urol 7, 603–609 (2010). https://doi.org/10.1038/nrurol.2010.165

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