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Der Urologe

, Volume 48, Issue 11, pp 1318–1329 | Cite as

Chronische PDE-5-Hemmung bei erektiler Dysfunktion

Neuer Therapieansatz mit täglicher Einmalgabe von Tadalafil
Übersichten

Zusammenfassung

Patienten mit erektiler Dysfunktion (ED) haben häufig auch ein erhöhtes kardiovaskuläres Risiko. Eine Schädigung des Gefäßendothels (endotheliale Dysfunktion) mit herabgesetzter Stickoxidsynthase- (NOS-)Aktivität und hierdurch verminderter Bioverfügbarkeit von Stickoxid (NO) scheint das pathogenetische Bindeglied zwischen ED und Herz-Kreislauf-Erkrankungen zu sein. Die zentrale Bedeutung des NO-Guanylatzyklase-cGMP-Mechanismus für den Erektionsvorgang spiegelt sich in der therapeutischen Wirksamkeit von Hemmstoffen der Phosphodiesterase-5 (PDE-5) bei der ED wider. Im Gegensatz zu anderen derzeit verfügbaren PDE-5-Hemmern mit Halbwertszeiten von ca. 4 h führt die lange Halbwertszeit von Tadalafil mit 17,5 h zu einer klinischen Wirksamkeit von bis zu 36 h, sodass eine Einzeldosis Tadalafil während dieses Zeitraums die Erektion verbessern kann. Die umfangreichsten klinischen Erfahrungen mit PDE-5-Hemmern liegen bislang mit einer bedarfsabhängigen Medikation vor, doch haben inzwischen mehrere Studien gezeigt, dass Tadalafil auch in niedrigen Dosierungen bei regelmäßiger, einmal täglicher Verabreichung sehr gut wirksam und verträglich ist. In 3 randomisierten, placebokontrollierten doppelblinden Multicenterstudien ließ sich anhand unterschiedlicher validierter Messparameter der erektilen Funktion belegen, dass Tadalafil in täglichen Dosen von 2,5, 5 oder 10 mg Placebo signifikant überlegen ist. In einer weiteren Studie war Tadalafil einmal täglich auch noch nach Versagen einer bedarfsgeleiteten Therapie wirksam.

In einer kontrollierten Cross-over-Studie gaben 72% der Patienten der täglichen Tadalafil-Therapie den Vorzug gegenüber einer bedarfsabhängigen Applikation, wobei hierfür insbesondere eine bessere sowie längere Wirksamkeit von Tadalafil mit der Ermöglichung eines wieder weitgehend spontanen Sexuallebens angegeben wurde. Eine Pilotstudie zeigte zudem, dass die regelmäßige Tadalafil-Einnahme im Gegensatz zur Bedarfsmedikation verschiedene Marker der Endothelfunktion an Penis- und anderen Gefäßen verbesserte.

Schlüsselwörter

Erektile Dysfunktion Endotheliale Dysfunktion PDE-5-Hemmer Tadalafil 

Chronic PDE-5 inhibition in patients with erectile dysfunction

New treatment approach using once daily Tadalafil

Abstract

Erectile dysfunction (ED) is often associated with increased cardiovascular risk. There is increasing evidence suggesting that dysfunction of the vascular endothelium with reduced bioavailability of nitric oxide (NO) may be the pathogenetic link between ED and cardiovascular disease. The crucial importance of the NO-guanylatecyclase-cGMP-phosphodiesterase pathway for penile erection is mirrored by the efficacy of phosphodiesterase-5 (PDE5) inhibitors in the treatment of ED. In contrast to other currently available PDE5 inhibitors with a half-life time of about 4 h Tadalafil has a half-life time of about 17.5 h resulting in erectile responsiveness for up to 36 h after 1 single dose. Most clinical experience has been reported with on-demand use of PDE-5 inhibitors, but meanwhile several studies were able to demonstrate that Tadalafil given daily in low (2.5 and 5 mg) doses is both highly effective and well-tolerated. In three randomized, double-blind, placebo-controlled multi-center trials, various validated measures of erectile function indicated that once daily Tadalafil at doses of 2.5, 5, and 10 mg was significantly superior to placebo.

In another mono-center trial, once daily Tadalafil has shown significant efficacy even after failure of on-demand treatment. In a controlled cross-over study of on-demand versus daily Tadalafil treatment, 72% of the patients preferred once daily administration, mainly because of superior and longer efficacy allowing a more spontaneous sexual life. Interestingly in a pilot study of on-demand versus chronic administration of Tadalafil for 4 weeks, only regular dosing improved several markers of endothelial function.

Keywords

Erectile dysfunction Endothelial dysfunction PDE-5 inhibitors Tadalafil 

Notes

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: Berater und Investigator für Lilly, Bayer, Pfizer und Janssen-Cilag. Trotz des möglichen Interessenkonflikts ist der Beitrag unabhängig und produktneutral.

Literatur

  1. 1.
    Feldman HA, Goldstein I, Hatzichristou DG et al (1994) Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 151:54–61PubMedGoogle Scholar
  2. 2.
    Porst HU, Sharlip H (2006) History and epidemiology of male sexual dysfunction; In: Porst H, Buvat J (eds) Standard practice in sexual medicine. Blackwell Publishing, London, pp 43–48Google Scholar
  3. 3.
    Althof SE (2002) Quality of life and erectile dysfunction. Urology 59:803–810CrossRefPubMedGoogle Scholar
  4. 4.
    Montorsi F, Briganti A, Salonia A et al (2003) Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 44:360–365CrossRefPubMedGoogle Scholar
  5. 5.
    Montorsi P, Ravagnani PM, Galli S et al (2006) Association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. Eur Urol 50:721–731CrossRefPubMedGoogle Scholar
  6. 6.
    Lue TF (2000) Erectile dysfunction. N Engl J Med 342:1802–1813CrossRefPubMedGoogle Scholar
  7. 7.
    Jensen J, Lendorf A, Stimpel H et al (1999) The prevalence and etiology of impotence in 101 male hypertensive outpatients. Am J Hypertens 12:271–275CrossRefPubMedGoogle Scholar
  8. 8.
    Bacon CG, Hu FB, Giovannucci E et al (2002) Association of type and duration of diabetes with erectile dysfunction in a large cohort of men. Diabetes Care 25:1458–1463CrossRefPubMedGoogle Scholar
  9. 9.
    Thompson IM, Tangen CM, Goodman PJ et al (2005) Erectile dysfunction and subsequent cardiovascular disease. JAMA 294:2996–3002CrossRefPubMedGoogle Scholar
  10. 10.
    El-Sakka AI, Morsy AM (2004) Screening for ischemic heart disease in patients with erectile dysfunction: role of penile Doppler ultrasonography. Urology 64:346–350CrossRefPubMedGoogle Scholar
  11. 11.
    Chiurlia E, D’Amico R, Ratti C et al (2005) Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol 46:1503–1506CrossRefPubMedGoogle Scholar
  12. 12.
    Kirby M, Jackson G, Simonsen U (2005) Endothelial dysfunction links erectile dysfunction to heart disease. Int J Clin Pract 59:225–229CrossRefPubMedGoogle Scholar
  13. 13.
    Vlachopoulos C, Aznaouridis K, Ioakeimidis N et al (2006) Unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease. Eur Heart J 27:2640–2648CrossRefPubMedGoogle Scholar
  14. 14.
    Montorsi P, Montorsi F, Schulman CC (2003) Is erectile dysfunction the „tip of the iceberg“ of a systemic vascular disorder? Eur Urol 44:352–354CrossRefPubMedGoogle Scholar
  15. 15.
    Vita JA, Keaney JF, Larson MG et al (2004) Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study. Circulation 110:3604–3609CrossRefPubMedGoogle Scholar
  16. 16.
    Clapp BR, Hingorani AD, Kharbanda RK et al (2004) Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res 64:172–178CrossRefPubMedGoogle Scholar
  17. 17.
    Saenz de Tejada I, Goldstein I, Azadzoi K et al (1989) Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 320:1025–1030CrossRefGoogle Scholar
  18. 18.
    Ignarro LJ, Bush PA, Buga GM et al (1990) Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 170:843–850CrossRefPubMedGoogle Scholar
  19. 19.
    Vallance P, Chan N (2001) Endothelial function and nitric oxide: clinical relevance. Heart 85:342–350CrossRefPubMedGoogle Scholar
  20. 20.
    Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58(3):488–520CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang X, Feng Q, Cote RH (2005) Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Invest Ophthalmol Vis Sci 46:3060–3066CrossRefPubMedGoogle Scholar
  22. 22.
    Porst H, Sharlip ID, Hatzichristou D et al (2006) Extended duration of efficacy of vardenafil when taken 8 hours before intercourse: a randomized, double-blind, placebo-controlled study. Eur Urol 50:1094–1094Google Scholar
  23. 23.
    McCullough AR, Steidle CP, Klee B et al (2008) Randomized, double-blind, crossover trial of sildenafil in men with mild to moderate erectile dysfunction: Efficacy at 8 and 12 hours postdose. Urology 71:686–692CrossRefPubMedGoogle Scholar
  24. 24.
    Porst H, Padma-Nathan H, Giuliano F et al (2003) Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: A randomized controlled trial. Urology 62:121–125CrossRefPubMedGoogle Scholar
  25. 25.
    Forgue ST, Patterson BE, Bedding AW et al (2006) Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 61:280–288CrossRefPubMedGoogle Scholar
  26. 26.
    Carson CC, Burnett AL, Levine LA et al (2002) The efficacy of sildenafil citrate (Viagra) in clinical populations: an update. Urology 60(2 Suppl 2):12–27CrossRefPubMedGoogle Scholar
  27. 27.
    Goldstein I, Lue TF, Padma-Nathan H et al (1998) Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 338:1397–1404CrossRefPubMedGoogle Scholar
  28. 28.
    Porst H, Rosen R, Padma-Nathan H et al (2001) The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res 13:192–199CrossRefPubMedGoogle Scholar
  29. 29.
    Brock GB, McMahon CG, Chen KK et al (2002) Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 168:1332–1336CrossRefPubMedGoogle Scholar
  30. 30.
    Rubio-Aurioles E, Porst H, Eardley I et al (2006) 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 3:1037–1049CrossRefPubMedGoogle Scholar
  31. 31.
    Tolrà JR, Campana JM, Ciutat LF, Miranda EF (2006) 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 3:901–909CrossRefPubMedGoogle Scholar
  32. 32.
    Rodríguez Vela L, Lledó García E, Rajmil O et al (2006) Tadalafil vs sildenafil patient preference in Spanish men with erectile dysfunction: results from an International Multicentric Study. Actas Urol Esp 30:67–79Google Scholar
  33. 33.
    Eardley I, Mirone V, Montorsi F et al (2005) 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 96:1323–1332CrossRefPubMedGoogle Scholar
  34. 34.
    Dean J, Hackett GI, Gentile V et al (2006) Psychosocial outcomes and drug attributes affecting treatment choice in men receiving sildenafil citrate and tadalafil for the treatment of erectile dysfunction: results of a multicenter, randomized, open-label, crossover study. J Sex Med 3:650–661CrossRefPubMedGoogle Scholar
  35. 35.
    Sommer E, Klotz T, Mathers M et al (2004) A comparative multicentre study of the maximum dose of sildenafil, tadalafil and vardenafil. Eur Urol Suppl 3(2):410Google Scholar
  36. 36.
    Porst H, Kleingarn M, Arnds S (2004) The two PDE5 inhibitors sildenafil and tadalafil - results of an independent intraindividual comparative trial. Eur Urol 3(Suppl 2):99Google Scholar
  37. 37.
    von Keitz A, Rajfer J, Segal S et al (2004) A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil. Eur Urol 45:499–507CrossRefGoogle Scholar
  38. 38.
    Porst H, Arnds S, Kleingarn M (2004) The 3 PDE5 inhibitors sildenafil, tadalafil and vardenafil: Results of an independent intraindividual comparative study. Eur Urol 3(Suppl 2):408Google Scholar
  39. 39.
    Govier F, Potempa AJ, Kaufman J et al (2003) A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther 25:2709–2723CrossRefPubMedGoogle Scholar
  40. 40.
    Ströberg P, Murphy A, Costigan T (2003) Switching patients with erectile dysfunction from sildenafil citrate to tadalafil: results of a European multicenter, open-label study of patient preference. Clin Ther 25:2724–2737CrossRefPubMedGoogle Scholar
  41. 41.
    Laties A, Sharlip I (2006) Ocular safety in patients using sildenafil citrate therapy for erectile dysfunction. J Sex Med 3:12–27CrossRefPubMedGoogle Scholar
  42. 42.
    Kloner RA, Hutter AM, Emmick JT et al (2003) Time course of the interaction between tadalafil and nitrates. J AM Coll Cardiol 42:1855–1860CrossRefPubMedGoogle Scholar
  43. 43.
    Porst H, Giuliano F, Glina S et al (2006) 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 50:351–359CrossRefPubMedGoogle Scholar
  44. 44.
    Montorsi F, Verheyden B, Meuleman E et al (2004) Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol 45:339–344CrossRefPubMedGoogle Scholar
  45. 45.
    Vernet D, Magee T, Qian A et al (2006) Phosphodiesterase type 5 is not upregulated by tadalafil in cultures of human penile cells. J Sex Med 3:84–94CrossRefPubMedGoogle Scholar
  46. 46.
    McMahon C (2005) Comparison of efficacy, safety and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2:415–427CrossRefPubMedGoogle Scholar
  47. 47.
    Dunn ME, Althof SE, Perelman MA (2007) Phosphodiesterase type 5 inhibitors‘ extended duration of response as a variable in the treatment of erectile dysfunction. Int J Impot Res 19:119–123CrossRefPubMedGoogle Scholar
  48. 48.
    Rosano GM, Aversa A, Vitale C et al (2005) Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 47:214–220CrossRefPubMedGoogle Scholar
  49. 49.
    Sorensen KE, Celermajer DS, Spiegelhalter DJ (1995) Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J 74:247–253CrossRefPubMedGoogle Scholar
  50. 50.
    Foresta C, Ferlin A, De Toni L et al (2006) Circulating endothelial progenitor cells and endothelial function after chronic Tadalafil treatment in subjects with erectile dysfunction. Int J Impot Res 18:484–488CrossRefPubMedGoogle Scholar
  51. 51.
    Dimmeler S, Zeiher AM (2004) Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? J Mol Med 82:671–677CrossRefPubMedGoogle Scholar
  52. 52.
    Sesti C, Florio V, Johnson EG, Kloner RA (2007) The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size. Int J Impot Res 19:55–61CrossRefPubMedGoogle Scholar
  53. 53.
    Schwarz ER, Kapur V, Rodriguez J et al (2007) The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. Int J Impot Res 19:139–148CrossRefPubMedGoogle Scholar
  54. 54.
    McMahon C (2004) Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to on-demand tadalafil. J Sex Med 1:292–300CrossRefPubMedGoogle Scholar
  55. 55.
    Rajfer J, Aliotta PJ, Steidle CP et al (2007) Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. Int J Impot Res 19:95–103CrossRefPubMedGoogle Scholar
  56. 56.
    Aversa A, Greco E, Bruzziches R et al (2007) Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res 19:200–207CrossRefPubMedGoogle Scholar
  57. 57.
    Porst H, Rajfer J, Casabé A et al (2008) Long-term safety and efficacy of tadalafil 5 mg dosed once daily in men with erectile dysfunction. J Sex Med 5:2160–2169CrossRefPubMedGoogle Scholar
  58. 58.
    Zumbé J, Porst H, Sommer F et al (2008) Comparable effect of once-daily versus on-demand vardenafil in men with mild-to-moderate erectile dysfunction. Eur Urol 54:204–212CrossRefPubMedGoogle Scholar
  59. 59.
    Jackson G, Kloner RA, Costigan TM et al (2004) Update on clinical trials of tadalafil demonstrates no increased risk of cardiovascular adverse events. J Sex Med 1:161–167CrossRefPubMedGoogle Scholar
  60. 60.
    Hatzichristou D, Gambla M, Rubio-Auroles E, Buvat J et al (2007) Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med 25:138–146CrossRefGoogle Scholar
  61. 61.
    Wright PJ (2006) Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract 60:967–975CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag 2009

Authors and Affiliations

  1. 1.Praxis für Urologie und AndrologieHamburgDeutschland
  2. 2.Medizinische AbteilungLilly Deutschland GmbHBad HomburgDeutschland

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