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Review

Advances in pharmacotherapy for erectile dysfunction and associated cardiac impact

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Pages 2281-2289 | Received 08 Aug 2016, Accepted 23 Sep 2016, Published online: 08 Oct 2016

References

  • Impotence NCC. NIH consensus development panel on impotence. JAMA. 1993;270:83–90.
  • Uckert S, Mayer ME, Stief CG, et al. The future of the oral pharmacotherapy of male erectile dysfunction: things to come. Expert Opin Emerg Drugs. 2007 May;12(2):219–228.
  • Gandaglia G, Briganti A, Jackson G, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol. 2014;65:968–978.
  • Lue TF. Erectile dysfunction. N Engl J Med. 2000;342(24):1802–1813.
  • Papatsoris AG, Triantafyllidis A, Gekas A. Prevalence of erectile dysfunction in the European Union. Asian J Androl. 2003 Sep;5(3):255.
  • Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120:151–157.
  • Lindau ST, Schumm LP, Laumann EO, et al. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357:762–774.
  • Corona G, Lee DM, Forti G, et al. EMAS Study Group. Age-related changes in general and sexual health in middle-aged and older men: results from the European male ageing study. J Sex Med. 2010;7:1362–1380.
  • Shamloul R, Ghanem H. Erectile dysfunction. Lancet. 2013;381:153–165.
  • Giuliano F, Droupy S. Erectile dysfunction. Prog Urol. 2013 Jul;23(9):629–637.
  • Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med. 2000;30:328–338.
  • Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol. 2004;43:1405–1411.
  • El-Sakka AI, Morsy AM, Fagih BI. Severity of erectile dysfunction could predict left ventricular diastolic dysfunction in patients without overt cardiac complaint. J Sex Med. 2011;8:2590–2597.
  • Vlachopoulos CV, Terentes-Printzios DG, Ioakeimidis NK, et al.. Prediction of cardiovascular events and all-cause mortality with erectile dysfunction: a systematic review and meta-analysis of cohort studies. Circ Cardiovasc Qual Outcomes. 2013;6:99–109.
  • Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of cardio- vascular disease: meta-analysis of prospective cohort studies. J Am Coll Cardiol. 2011;58:1378–1385.
  • Nehra A, Jackson G, Miner M, et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012;87:766–778.
  • Dahabreh IJ, Paulus JK. Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis. JAMA. 2011;305:1225–1233.
  • Montorsi P, Ravagnani PM, Galli S, et al. Association between erectile dysfunction and coronary artery disease: role of coronary clinical presentation and extent of coronary vessels involvement: the COBRA trial. Eur Heart J. 2006;27(22):2632–2639.
  • Hatzimouratidis K, Salonia A, Adaikan G, et al. Pharmacotherapy for erectile dysfunction: recommendations from the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med. 2016 Apr;13(4):465–488.
  • Hodges LD, Kirby M, Solanki J, et al. The temporal relationship between erectile dysfunction and cardiovascular disease. Int J Clin Pract. 2007;61(12):2019–2025.
  • Patatsoris AG, Korantzopoulos PG. Hypertension, antihypertensive therapy, and erectile dysfunction. Angiology. 2006 Jan-Feb;57(1):47–52.
  • Carson CC, Lue TF. Phosphodiesterase type 5inhibitors for erectile dysfunction. BJU Int. 2005;96:257–280.
  • Viagra®. Full prescribing information, sildenafil citrate. New York (NY): Pfizer; 2005.
  • Hatzimouratidis K, Amar E, Eardley I, et al. European Association of Urology guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010;57:804–814.
  • ClinicalTrials.gov. A service of the U.S. National Institutes of Health. [ cited 2016 Jun 1]. Available from: https://clinicaltrials.gov/
  • Guazzi M, Vicenzi M, Arena R, et al. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011;4:8–17.
  • Giannetta E, Isidori AM, Galea N, et al. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012;125:2323–2333.
  • Redfield M, Chen H, Borlaug B, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268–1277.
  • Andersen M, Ersboll M, Axelsson A, et al. Sildenafil and diastolic dysfunction after acute myocardial infarction in patients with preserved ejection fraction: the Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction (SIDAMI) trial. Circulation. 2013;127:1200–1208.
  • Giannetta E, Feola T, Gianfrilli D, et al. Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials. BMC Med. 2014;12:185.
  • Schwartz BG, Levine LA, Comstock G, et al. Cardiac uses of phosphodiesterase-5 inhibitors. J Am Coll Cardiol. 2012;59:9–15.
  • Salloum FN, Abbate A, Das A, et al. Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol. 2008;294:H1398–406.
  • Takimoto E, Champion H, Li M, et al. Chronic inhibition of cyclic GMP phosphodi- esterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11:214–222.
  • Kim K, Kim Y, Ohn J, et al. Long-term effects of sildenafil in a rat model of chronic mitral regurgitation: benefits of ventricular remodeling and exercise capacity. Circulation. 2012;125:1390–1401.
  • Herrmann HC, Chang G, Klugherz BD, et al.. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med. 2000;342:1622–1626.
  • Arruda-Olson A, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized cross- over trial. JAMA. 2002;287:719–725.
  • Gazzaruso C, Solerte S, Pujia A, et al. Erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease: a potential protective role for statins and 5-phosphodiesterase inhibitors. J Am Coll Cardiol. 2008;51:2040–2044.
  • Salloum FN, Ockaili RA, Wittkamp M, et al. Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits. J Mol Cell Cardiol. 2006 Mar;40(3):405–411.
  • Morales AM, Casillas M, Turbi C. Patients’ preference in the treatment of erectile dysfunction: a critical review of the literature. Int J Impot Res. 2011;23(1):1–8.
  • Sesti C, Florio V, Johnson EG, et al.. The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size. Int J Impot Res. 2007;19:55–61.
  • Evans J, Hill S. A comparison of the available phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction: a focus on avanafi. Patient Prefer Adherence. 2015;9:1159–1164.
  • US Food and Drug Administration. FDA approves Stendra for erectile dysfunction. Available from: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm302140.htm
  • Limin M, Johnsen N, Hellstrom WJ. Avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. Expert Opin Investig Drugs. 2010;19:1427–1437.
  • Goldstein I, Jones LA, Belkoff LH, et al. Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus. Mayo Clin Proc. 2012;87:843–852.
  • Alwaal A, Al-Mannie R, Carrier S. Future prospects in the treatment of erectile dysfunction: focus on avanafil. Drug Des Devel Ther. 2011;5:435–443.
  • Doh H, Shin CY, Son M, et al. Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. Arch Pharm Res. 2002;25(6):873–878.
  • Moon Du G, Yang DY, Lee CH, et al. A therapeutic confirmatory study to assess the safety and efficacy of Zydena (udenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus. J Sex Med. 2011;8(7):2048–2061.
  • Paick JS, Kim SW, Park YK, et al. The efficacy and safety of udenafil [Zydena] for the treatment of erectile dysfunction in hypertensive men taking concomitant antihypertensive agents. J Sex Med. 2009;6(11):3166–3176.
  • Chung BH, Lee JY, Lee SH, et al. Safety and efficacy of the simultaneous administration of udenafil and an alpha-blocker in men with erectile dysfunction concomitant with BPH/LUTS. Int J Impot Res. 2009;21(2):122–8 72.
  • Zhao C, Kim SW, Yang DY, et al. Efficacy and safety of once-daily dosing of udenafil in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo- controlled trial. Eur Urol. 2011;60(2):380–387.
  • Kim K-H, Kim H-K, Hwang I-C, et al. ULTIMATE-SHF trial (UdenafiL Therapy to Improve symptoMAtology, exercise Tolerance and hEmodynamics in patients with chronic systolic heart failure): study protocol for a randomized, placebo-controlled, double-blind trial. Trials. 2013;14:188.
  • Lee J, Yoo HH, Rhim KJ, et al. Metabolism and excretion of 5-ethyl-2- {5-[4-(2hydroxyethyl)piperazine-1- sulfonyl]-2-propoxyphenyl}-7-propyl- 3,5-dihydropyrrolo[3,2-d]-pyrimidin-4- one (SK3530) in rats. Rapid Commun Mass Spectrom. 2007;21(7):1139–1149.
  • Paick JS, Ahn TY, Choi HK, et al. Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction. J Sex Med. 2008;5(11):2672–2680.
  • Park HJ, Choi HK, Ahn TY, et al. Efficacy and safety of oral mirodenafil in the treatment of erectile dysfunction in diabetic men in Korea: a multicenter, randomized, double-blind, placebo-controlled clinical trial. J Sex Med. 2010;7:2842–2850.
  • Paick JS, Kim JJ, Kim SC, et al. Efficacy and safety of mirodenafil in men taking antihypertensive medications. J Sex Med. 2010;7:3143–3152.
  • Chung JH, Kang DH, Oh CY, et al. Safety and efficacy of once daily administration of 50 mg mirodenafil in patients with erectile dysfunction: a multicenter, double-blind, placebo controlled trial. J Urol. 2013;189:1006–1013.
  • Glina S, Fonseca GN, Bertero EB, et al. Efficacy and tolerability of lodenafil carbonate for oral therapy of erectile dysfunction: a phase III clinical trial. J Sex Med. 2010;7(5):1928–1936.
  • Mendes GD, dos Santos Filho HO, dos Santos Pereira A, et al. A phase I clinical trial of lodenafil carbonate, a new phosphodiesterase type 5 (PDE5) inhibitor, in healthy male volunteers. Int J Clin Pharmacol Ther. 2012;50:896–906.
  • Polonio IB, Acencio MM, Pazetti R, et al. Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats. J Bras Pneumol. 2014 Jul-Aug;40(4):421–424.
  • Albersen M, Shindel A, Mwamukonda K, et al.. The future is today: emerging drugs for the treatment of erectile dysfunction. Expert Opin Emerg Drugs. 2010;15(3):467–480.
  • SLx-2101; Pharmaprojects-copyright to citeline drug intelligence (an informa business).
  • Chan JS, Kim DJ, Ahn CH, et al. Clavulanic acid stimulates sexual behaviour in male rats. Eur J Pharmacol. 2009 May 1;609(1–3):69–73.
  • Rexahn Pharmaceuticals. Efficacy study of RX-10100 to treat Erectile Dysfunction (ED). Bethesda (MD): National Library of Medicine (US). ClinicalTrials.gov; 2009.
  • King SH, Mayorov AV, Balse-Srinivasan P, et al.. Melanocortin receptors, melanotropic peptides and penile erection. Curr Top Med Chem. 2007;7(11):1098–1106.
  • Hellstrom WJ. Clinical applications of centrally acting agents in male sexual dysfunction. Int J Impot Res. 2008 Jul;20(Suppl 1):S17–23.
  • Safarinejad MR, Hosseini SY. Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study. J Urol. 2008 Mar;179(3):1066–1071.
  • Diamond LE, Earle DC, Rosen RC, et al. 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(1):51–59.
  • Hellstrom W, Gittelman M, Zinner N, et 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 [abstract]. 9th Congress of the European Society for Sexual Medicine; Vienna, Austria. J Sex Med. 2006;117.
  • Rosen RC, Diamond LE, Earle DC, et al. Evaluation of the safety, pharmacokinetics and pharmacodynamics 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;16:51–59.
  • Patel MV, Kolasa T, Mortell K, et al. Discovery of 3- methyl-N-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-bipyridine]-1′-ylmethyl)benzam ide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction. J Med Chem. 2006 Dec 14;49(25):7450–7465.
  • Brioni J, Moreland R, Cowart M, et al. Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats. Proc Natl Acad Sci USA. 2004;101(17):6758–6763.
  • Hatzimouratidis K, Hatzichristou D. Looking to the future for erectile dysfunction therapies. Drugs. 2008;68(2):231–250.
  • Lasker G, Pankey E, Frink T, et al. The sGC activator BAY 60-2770 has potent erectile activity in the rat. Am J Physiol Heart Circulatory Physiol. 2013;304(12):H1670–H1679.
  • Costell M, Ancellin N, Bernard R, et al. Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress. Front Pharmacol. 2012;3:128. DOI:10.3389/fphar.2012.00128.
  • Kalsi J, Rees R, Hobbs A, et al. BAY41-2272, a novel nitric oxide independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro. J Urol. 2003 Feb;169(2):761–766.
  • Miller L, Nakane M, Hsieh G, et al. A-350619: a novel activator of soluble guanylyl cyclase. Life Sci. 2003 Jan 17;72(9):1015–1025.
  • Oudot A, Behr-Roussel D, Poirier S, et al. Combination of BAY 60-4552 and vardenafil exerts proerectile facilitator effects in rats with cavernous nerve injury: a proof of concept study for the treatment of phosphodiesterase type 5 inhibitor failure. Eur Urol. 2011;60(5):1020–1026.
  • Albersen M, Linsen L, Tinel H, et al. Synergistic effects of BAY 60-4552 and vardenafil on relaxation of corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure. J Sex Med. 2013;10(5):1268–1277.
  • Bayer Healthcare AG. A prospective, randomized, double-blind, double- dummy, placebo and active controlled, multicenter study assessing the efficacy and safety of the combination BAY 60 4552/ vardenafil compared to vardenafil (20 mg) for the treatment of erectile dysfunction not sufficiently responsive to standard therapy with PDE5 inhibitors. Bethesda (MD): National Library of Medicine (US), ClinicalTrials.gov; 2014.
  • Dasgupta A, Bowman L, D’Arsigny C, et al. Soluble Guanylate Cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Clin Pharmacol Ther. 2015 Jan;97(1):88–102.
  • Stasch J, Evgenov O. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol. 2013;218:279–313.
  • Schwappacher R Kilic A Kojonazarov B et al. A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension. J Biol Chem. 2013;288:16557–16566.
  • Christ G. Rehman J Day N, et al. Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am J Physiol. 1998;275:H600–H608.
  • Melman A, Zhao W, Davies K, et al.. The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo. J Urol. 2003;170:285–290.
  • Melman A Biggs G Davies K, et al. Gene transfer with a vector expressing Maxi-K from a smooth muscle specific promoter restores erectile function in the aging rat. Gene Ther. 2008;15:364–370.
  • Christ G Andersson KE Williams K, et al. Editorial comment on: smooth-muscle-specific gene transfer with the human maxi-K channel improves erectile function and enhances sexual behavior in atherosclerotic cynomolgus monkeys. Eur Urol. 2009;56:1066.
  • Melman A, Bar-Chama N, McCullough A, et al.. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum Gene Ther. 2006;17(12):1165–1176.
  • Melman A, Davies K. Gene therapy in the management of erectile dysfunction (ED): past, present, and future. Scientific World J. 2009;9:846–854.
  • Bentzen B, Olesen S, Ronn L, et al. BK channel activators and their therapeutic perspectives. Front Physiol. 2014;5:389.
  • Aon M, Cortassa S, Wei A, et al. Energetic performance is improved by specific activation of K+ fluxes through K(Ca) channels in heart mitochondria. Biochim Biophys. 2010; Acta 1797(1):71–80.
  • Borchert G, Hlaváčková M, Kolář F. Pharmacological activation of mitochondrial BK(Ca) channels protects isolated cardiomyocytes against simulated reperfusion-induced injury. Exp Biol Med (Maywood). 2013 Feb;238(2):233–241.
  • Bentzen B, Osadchii O, Jespersen T, et al. Activation of big conductance Ca2+-activated K+ channels (BK) protects the heart against ischemia–reperfusion injury. Pflugers Arch. 2009 Mar;457(5):979–988.
  • Kun A, Matchkov VV, Stankevicius E, et al. NS11021, a novel opener of large- conductance Ca(2+)-activated K(+) channels, enhances erectile responses in rats. Br J Pharmacol. 2009;158(6):1465–1476.
  • Király I, Pataricza J, Bajory Z, et al.. Involvement of large-conductance Ca(2+) -activated K(+) channels in both nitric oxide and endothelium-derived hyperpolarization-type relaxation in human penile small arteries. Basic Clin Pharmacol Toxicol. 2013;113(1):19–24.
  • Pauwels B, Boydens C, Brouckaert P, et al. Oximes induce erection and are resistant to oxidative stress. J SexMed. 2015;12:906–915.
  • Grievink H, Zeltcer G, Drenger B, et al. Protection by nitric oxide donors of isolated rat hearts is associated with activation of redox metabolism and ferritin accumulation. PLoS One. 2016 Jul 22;11(7). doi:10.1371/journal.pone.0159951.
  • Lukowski R, Krieg T, Rybalkin S, et al. Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond. Trends Pharmacol Sci. 2014;35(8):404–413.
  • Lukowski R Rybalkin SD Loga F, et al. Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proc Natl Acad Sci. 2010;107:5646–5651.

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