Le onde d’urto nella disfunzione erettile: la terapia del futuro? Marco Franco

Erectile funcion: the anatomical substrate Progenitors Progenitors Neurons Endothelial cells Smooth muscle cells Vessels Homeostasis (Physiology)  Remodelling (Pathology)

Intracavernosal injections Limits Side effects Lack of durable effect on the spontaneous improvement of erectile function. “Difficult-to-treat” patients Although the majority of ED patients can be satisfactorily treated with phosphodiesterase type 5 inhibitors (PDE5), a substantial population (30– 40%) cannot. This includes patients who are intolerant to PDE5 inhibitors’ side effects, taking nitrate medication for angina, or having certain types of ED refractory to PDE5 inhibitors. Intracavernosal injections Penile implants.

2013: New

Low Intensity ESWT (LIESWT) & Vessels The evidences In vivo pre-clinical evidences Non ED animal models ED animal model Clinical evidences on ED patients

Porcine model of chronic myocardial ischemia 2004 LI-ESWT Control Porcine model of chronic myocardial ischemia

Control LI-ESWT Collateral vessels Coronary angiography Ventriculography Nishida T., et al., Circulation, 2004

progenitor cells (EPCs) homing 2006 SDF-1 Endothelial progenitor cells (EPCs) homing VEGF Aicher A., et al., Circulation, 2006

N (n=8) DM (n=8) Streptozocin DM + SW (n=8) J Sex med, 2013

nNOS expression When compared with DM rats, shockwave-treated rats displayed significantly higher numbers of nNOS-positive nerves in different compartments of the erectile tissue, including the dorsal nerves, around the dorsal arteries, and in the corpora cavernosa.

Endothelial content ESWT was able to significantly restore the endothelial contents in both the cavernous sinusoids and arteries compartments.

ESWT is able to significantly restore the smooth muscle content

Mesenchymal stem cells Increased recruitment of MSCs into the erectile tissue.

? ESWT Improved erectile function Vasculogenic growth factors - chemoattractors Mechanosensors membrane receptor kinases, integrins, G proteins, ion channels, intercellular junction proteins, membrane lipids (e.g., those associated with caveolae), and the cytoskeleton Increased homing of precursors Restoration of erectile tissue integrity Neoangiogenesis Improved erectile function

ESWT Cavitation Shear stress Mechanosensors Improved erectile function Vasculogenic growth fctors - chemoattractors Mechanosensors membrane receptor kinases, integrins, G proteins, ion channels, intercellular junction proteins, membrane lipids (e.g., those associated with caveolae), and the cytoskeleton Increased homing of precursors Restoration of erectile tissue integrity Neoangiogenesis Improved erectile function

Clinical evidences

2010 Professor Yoram Vardi 2012 2012

Medispec ED 1000

Pilot study 20 men with vasculogenic ED The inclusion criteria: History of ED for at least 6 mo Abnormal 2-night nocturnal penile tumescence (NPT) parameters PDE5-I responders IIEF-ED domain score between 5–19. The exclusion criteria: Psychogenic ED (normal NPT parameters) Any neurologic pathology Prior radical prostatectomy, and recovery from any cancer within the past 5 yr.

4-wk PDE5-I washout period The penis was manually stretched; the shockwaves were delivered to the distal, mid, and proximal penile shaft, and the left and right crura. 300 shocks per treatment point (1500 per session) at an energy density of 0.09 mJ/mm2 and a frequency of 120/min IIEF = International Index of Erectile Function; QEQ = Quality of Erection Questionnaire; SEAR = Self-Esteem and Relationship Questionnaire; RS = rigidity score; NPT = nocturnal penile tumescence; FMD = flow-mediated dilatation; EDITS = Erectile Dysfunction Inventory of Treatment Satisfaction. Vardi Y., et a., Eur Urol., 2010

Results High response rate (>70%) (higher than that of any previously published placebo-controlled trial in men with ED) Vardi Y., et a., Eur Urol., 2010

Enhanced penile perfusion Results Enhanced penile perfusion Vardi Y., et a., Eur Urol., 2010

Long-term follow up At the 3- and 6-mo follow-up examinations, 10 men reported that they had spontaneous erections that were sufficient for penetration and did not require PDE5-I support before sexual intercourse. None of the study participants reported any pain during the treatment and follow-up periods, and no adverse effects were recorded. Vardi Y., et a., Eur Urol., 2010

N= 20 N=40 Vardi Y., et al., The Journal of Urology, 2012

Ilan Gruenwald et al., J Sex Med, 2012

Improved penile endothelial function Ilan Gruenwald et al., J Sex Med, 2012

Ongoing Clinical Trials Extracorporeal Shock Wave Therapy With a Wide Focus Probe for the Treatment of Erectile Dysfunction Low Intensity Extracorporeal Shock Wave Therapy for the Treatment of Erectile Dysfunction- 4 Arms Low Intensity Shock Wave Therapy (LI-ESWT) for Erectile Dysfunction in Post Radical Prostatectomy Patients Not Responding to PDE5 Inhibitors (LI-ESWT)

Conclusions & Future directions

Intracavernosal injections Limits Side effects Lack of durable effect on the spontaneous improvement of erectile function. “Difficult-to-treat” patients Although the majority of ED patients can be satisfactorily treated with phosphodiesterase type 5 inhibitors (PDE5), a substantial population (30– 40%) cannot. This includes patients who are intolerant to PDE5 inhibitors’ side effects, taking nitrate medication for angina, or having certain types of ED refractory to PDE5 inhibitors. Intracavernosal injections Penile implants.

Conclusioni 1. DE Lieve – Medio 2. DE endoteliale 3. Pazienti difficili/impossibili da trattare con terapia orale ° Nitrati ° Con effetti collaterali ° Non effetti duraturi nel tempo ° Che intendono essere “curati” definitivamente 4. Ipotesi affascinante: associazione terapeutica