Management Of Erectile Dysfunction

Erectile Dysfunction Treatment options Tarek Anis Prof. of Andrology, Cairo University PASSM President

Incidence of Erectile Dysfunction

Prevalence of erectile dysfunction

Prevalence of erectile dysfunction 18! of all men above 20 years

77.6%

80%

60.2%

60%

43.7% 40%

23.9% 20%

6.5%

3.8%

8.2%

0%

20-29

30-39

40-49

50-59

60-69

70-74

>75

International Index of Erectile Function IIEF Score Over the past 6 months:

1

How do you rate your confidence that you could get an erection? 1 Very Low

2

5 Very High

2 A few times

3 Sometimes

4 Most times

5 Almost always or always

1 Almost never or never

2 A few times

3 Sometimes

4 Most times

5 Almost always or always

During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? 0 Did not attempt

5

4 High

During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? 0 Did not attempt

4

3 Moderate

When you had erections with sexual stimulation, how often were your erections hard enough for penetration? 0 No sexual activity 1 Almost never or never

3

2 Low

1 Extremely difficult 2 Very difficult

3 Difficult

4 Slightly difficult

5 Not difficult

When you attempted sexual intercourse, how often was it satisfactory to you? 0 Did not attempt

1 Almost never or never

2 A few times

3 Sometimes

4 Most times

5 Almost always or always

Erection Hardness Score Severe ED

Moderate ED

Mild ED

No ED

(IIEF5: ! 10)

(IIEF5: 11–15)

(IIEF5: 16–20)

(IIEF5: >20)

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Penis is hard but not hard enough for penetration

Penis is hard enough for penetration but not completely hard

Penis is completely hard and fully rigid

Penis is larger but not hard

Goldstein I et al. N Engl J Med 1998;338:1397–1404. Rosen RC et al. Int J Impot Res 1999; 319–26.

Major Risk Factors of Erectile dysfunction

Major Risk Factors of Erectile dysfunction Aging Chronic disease Cardiovascular disease, hypertension, diabetes, lower urinary tract symptoms, and depression

Medications Thiazide diuretics, beta"blockers, selective serotonin reuptake inhibitors

Lifestyle Stress, alcohol and drug abuse, smoking, obesity, and sedentary lifestyle

WHO Treatment Recommendation 1 Lifestyle Modification

Stop smoking Limit or avoid alcohol Follow healthy diet Exercise regularly Reduce weight Get adequate sleep

2

3

WHO Treatment Recommendation 1

2

Lifestyle Modification Drug Therapy Modifications

Antihypertensives/diuretics Selective serotonin"reuptake inhibitors Hormonal agents #eg, anti"androgens$ H2"receptor

3

WHO Treatment Recommendation 1

2

3

Lifestyle Modification Drug Therapy Modifications Psychosocial Counseling

Anxiety reduction/desensitization Cognitive"behavioral interventions Sexual stimulation techniques Interpersonal assertiveness/couples’ communication training

WHO Treatment Recommendation 1

2

Lifestyle Modification Drug Therapy Modifications Psychosocial Counseling Androgen Replacement

Transdermal testosterone Gel or scrotal, buccal, and non"scrotal patches Intramuscular #IM$ injection Subcutaneous implant Oral testosterone

3

WHO Treatment Recommendation 1 Lifestyle Modification Drug Therapy Modifications Psychosocial Counseling Androgen Replacement Oral PDE5 Inhibitors

Sildenafil #Viagra®$ Tadalafil #Cialis®$ Vardenafil #Levitra®$

2

3

WHO Treatment Recommendation 1 Lifestyle Modification Drug Therapy Modifications Psychosocial Counseling Androgen Replacement Oral PDE5 Inhibitors

2 Intracavernosal injection

3

WHO Treatment Recommendation 1 Lifestyle Modification Drug Therapy Modifications Psychosocial Counseling Androgen Replacement Oral PDE5 Inhibitors

2 Intracavernosal injection MUSE

3

WHO Treatment Recommendation 1 Lifestyle Modification Drug Therapy Modifications Psychosocial Counseling Androgen Replacement Oral PDE5 Inhibitors

2 Intracavernosal injection MUSE Vacuum device

3

WHO Treatment Recommendation 1 Lifestyle Modification Drug Therapy Modifications Psychosocial Counseling Androgen Replacement Oral PDE5 Inhibitors

2 Intracavernosal injection

3 Penile prosthesis Revascularization

MUSE Vacuum device

First"Line Therapy for Management of ED

Approved and emerging PDE5 inhibitors Sildenafil

Pfizer

Approved for ED and PAH

Vardenafil

Bayer

Approved for ED

Tadalafil

Eli Lilly

Approved for ED

Udenafil

Dong Pharmaceutical Co Ltd

Approved for ED in Korea, Phase 3 in US

Avanafil

Vivus

Phase 2

SLX"2101

Surface Logics

Phase 2

Tadalafil

Vardenafil

Sildenafil

Mechanism of action Sexual Stimulation

Endothelial cell

Cavernous nerve

Stimulation Inhibition

Smooth muscle cell Endoplasmic reticulum Nitric oxide

Decreased Ca2+

cGMP!specific protein Kinase

Guanylate cyclase

cGMP

GTP

Ca2+

K+

Smooth muscle relaxation

PDE5 5’ GMP

K+ PDE5 inhibitor site of action

Ca2+

Image by Christine Kenney, from “Erectile dysfunction: management update,” Reprinted from CMAJ ; 170#9$, page#s$ 1429%1437,

Chemical Structure O

O O

N

HN

O

N

HN N

N

O

O

N

N

N

O

N

O

S

O

N

HN

N

N

O

S O

H N

H 2N

O 0H

O O

O O

N

Sildenafil

N

Vardenafil Tadalafil: a new agent for erectile dysfunction. Brock, G. (2003). Can J Urol, 10 Suppl 1, 17-22.

N

N

Tadalafil

P

O 0H

cGMP

Pharmacokinetic Profile

& C max with food

t max #h$ t 1/2 #h$ Presence in the body #h$ Therapeutic window #h$

Viagra

Cialis

Levitra

29!

no change

20!

1

2

1

3"5

17.5

~4

24 4

72 24

24 4

Metabolism The 3 drugs are metabolized by CYP3A4, a member of the Cytochrome P450 family Several drugs are known to inhibit this enzyme, such as the ketoconazole, erythromycin Any of these drug can result in elevated maximum plasma concentrations #Cmax$ of PDE5 inhibitors. Dose reduction of the PDE5 inhibitors is mandatory when they are being taken concomitantly with these drugs.

E'cacy of PDE5 inhibitors

Number of erections / month

VIAGRA 50 mg

Placebo

1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA for the Sildenafil Study Group. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397-1404.

Erection time in minutes

Time of Strong Erection

VIAGRA 100 mg

Placebo

1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA for the Sildenafil Study Group. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397-1404.

! increase

Ability to penetrate

VIAGRA

Placebo

1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA for the Sildenafil Study Group. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397-1404.

! increase

Time of maintenance of erection

VIAGRA

Reference: 1. Data on file. Pfizer Inc., New York, NY.

Placebo

! increase

Successful intercourse completion

VIAGRA

Placebo

Pooled data from Protocols 148-106 and 148-364 (12-week fixed dose studies) that included 370 patients. Patients responded to Event Log Question 3: Did you have successful sexual intercourse?

! increase

Reliability to have & Maintain Erection

VIAGRA Data pooled from flexible-dose, placebo-controlled, parallel-group studies with 6129 patients

Placebo

! increase

Total satisfaction

VIAGRA Data pooled from flexible-dose, placebo-controlled, parallel-group studies with 6129 patients

Placebo

Total Satisfaction

1 year

2 years

3 years

4 years

McMurray JG, Feldman RA, Auerbach SM, deRiesthal H, Wilson N. Long-term effectiveness and tolerability of Viagra ® (sildenafil citrate) in men with erectile dysfunction. Int J Impot Res. 2002;14(suppl 3):S104.

Side e(ects of PDE5 inhibitors

Phosphdiestrase Families Family

Regulatory Regions Calmodulin-binding sites

1

Conserved Catalytic Domain

Calmodulin-stimulated cAMP/cGMP PDE

P

cGMP-binding sites

cGMP-stimulated cAMP/cGMP PDE

2 cGMP-inhibited cAMP/cGMP PDE

Membrane association region

3

P

URC sites

4

P

cGMP-binding sites

5

cAMP-specific Rollpram-inhibited PDE cGMP-binding cGMP-specific PDE

P

cGMP-binding sites

6

Photoreceptor cGMP-specific PDE

7

cAMP-specific Rollpram-insensitive PDE

8

cAMP-specific PDE IBMX-insensitive

9

High affinity cAMP/cGMP PDE

cGMP-binding sites?

10 cGMP-binding site?

11

cGMP-binding cAMP/cGMP PDE cAMP/cGMP PDE

Selectivity Potency against PDE5

Selectivity Ratio

= Potency against other PDEs =

The smaller the number the less selective the drug is for PDE5 compared with the other isoenzyme

IC50 for PDE5 IC50 for other PDEs

Selectivity of PDE5 inhibitors IC50(nM)

PDE5A

PDE1

PDE2A

PDE3B

PDE4B

PDE6

PDE7B

PDE8

PDE9A

PDE10A

PDE11A

Vardenafil

0.89

121

>10000

2400

2055

11

4600

>10000

3370

1000

308

RatioX/5

1

136

>10000

2696

2308

15

5168

>100000

3786

1123

346

Sildenafil

8.5

350

>10000

>10000

3190

49

>10000

>1000

>10000

3800

1725

RatioX/5

1

41

>1000

>1000

375

7.4

>1000

>1000

>1000

447

203

Tadalafil

9.4

>10000

>10000

>10000

>10000

n.d.

>10000

>10000

>10000

>10000

67

RatioX/5

1

>1000

>1000

>1000

>1000

780

>1000

>1000

>1000

>1000

7.1

E Bischo", Potency, selectivity, and consequences of nonselectivity of PDE inhibition. International Journal of Impotence Research #2004$ 16, S11"S14.

Important PDE families

E(ect on PDE 6 Sildenafil is about 10 times more selective for PDE5 than for PDE6. Tadalafil is more selective for PDE5 than PDE6 compared with Sildenafil and Vardinafil. Sildenafil may be associated with visual disturbances "" blue hue, brightness, and blurring of vision. Infrequent reports of mild haziness, increased brightness of light, and color abnormalities have been reported with Vardenafil. Visual abnormalities have been rarely reported with Tadalafil

Rods sense brightness Cones sense color

PDE11 Localization in Human Tissues PDE11 occurs at highest levels in skeletal muscle, the testis, pituitary, pancreas, heart, prostate and salivary glands Testis : Germinal epithelium, i.e., spermatogonia, spermatocytes and spermatids, and interstitial #Leydig$ cells

Pituitary : acidophils #somatotrophs and lactotrophs$ of the anterior pituitary

SG=spermatogonia ST=spermatid IC=interstitial cells

AF

B

SG ST

SG

ST

IC

E(ects on Skeletal Muscles In tadalafil clinical trials, back pain or myalgia occurred 12 to 24 hours after dosing and typically resolved within 48 hours Back pain/myalgia associated with tadalafil treatment was characterized by bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency

Nucleus Endomysium Striation

E(ect on spermatogenesis AUA Clinical Guidelines PDE11 is present in the anterior pituitary and the testes. While studies, to date, have demonstrated no e(ect on spermatogenesis when PDE5 inhibitors are administered daily for 6 months in healthy individuals, further assessment of the e(ect of PDE5 inhibitors that cross react with PDE11 in patients with abnormal spermatogenesis is needed.

2005! "American Urological Association Education and Research!, "Chapter 1-p 28

PDE5 Inhibition Related Adverse Events Headache

Dyspepsia

Flushing

Adverse E(ects Related to PDE6 and PDE11 Inhibition Abnormal Vision

Myalgia & back pain

Abnormal Spermatogenesis

Sildenafil

3%

-ve

-ve

Vardenafil

2%

-ve

-ve

0.1%

5-12%

?

Tadalafil

PDE"5 Inhibitors and NAION In March 2005, a series of 7 patients, who had typical features of nonarteritic anterior ischemic optic neuropathy within 36 hours after ingestion of PDE5 inhibitors s was reported Two months later, the FDA advised healthcare professionals of a potential risk of sudden vision loss that may be attributed to use of PDE5 inhibitors. As of May, 2005, the FDA had received a total of 43 post"marketing reports of NAION in patients using PDE5 inhibitors

PDE"5 Inhibitors and NAION On July, 2005, the FDA approved updated labeling for sildenafil, tadalafil, and vardenafil to reflect a small number of postmarketing NAION cases FDA advises patients to stop taking these medicines, and call a doctor right away if they experience sudden decreased vision in one or both eyes. Patients considering taking these products should inform their doctors if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of recurrance

Pathogenesis NAION appears to be a multifactorial disease. Numerous risk factors, both systemic and local to the optic nerve, have been reported in association with the development of NAION. It has been suggested some of these risk factors #Cardiovascular and ocular$ predispose a patient to the development of NAION, while other risk factors #Nocturnal Hypotension and Sleep Apnea$ precipitate NAION in at"risk patients.

Risk Factors Systemic Factors Aging Hypertension Diabetes mellitus Hyperlipidemia Smoking Cerebrovascular disease Ischemic heart disease Systemic atherosclerosis Nocturnal hypotension Gastrointestinal ulcers Anemia Hypercoagulable state Thyroid disease Chronic obstructive pulmonary disease Surgery Sleep apnea Embolic disease

Ocular/optic nerve factors Vasospasm and impaired autoregulation of the optic nerve vasculature Rise in intraocular pressure Crowded optic disc ("discat-risk")

Drugs Angiotensin-converting enzyme (ACE) inhibitors Alpha-blockers Beta-blockers, including eyedrops Calcium-channel blockers Interferon-alpha Nasal decongestants Amiodarone Amitriptyline Phentermine Sumatriptan PDE5 inhibitors

Dimitris Hatzichristou, Phosphodiesterase 5 Inhibitors and Nonarteritic Anterior Ischemic Optic Neuropathy #NAION$: Coincidence or Causality? Journal of Sexual Medicine, Volume 2 Issue 6 Page 751 " November 2005

Number of Reported NAION Cases Viagra

Cialis

4 1

Levitra

3 5

38 Number of reported NAION Cases

27 Number of PDE5 inhibitors users in Millions

Nocturnal systemic hypotension The relative hypotension that normally occurs with sleep may chronically compromise optic disc circulation, in patients with heightened nocturnal drops in blood pressure or with hypertension, where optic disc circulation autoregulatory mechanisms are impaired. This e(ect could be heightened with antihypertensive or other medications #especially if administered at night$ that further exacerbate the nocturnal drop in blood pressure. This combination of hypertension during the day and hypotension during sleep could play a role in either the development or progression of NAION

PDE"5 Inhibitors and NAION The FDA statement concluded, "At this time, it is not possible to determine whether these oral medicines for ED were the cause of the loss of eyesight or whether the problem is related to other factors such as high blood pressure or diabetes, or to a combination of these problems."

Optimizing PDE5 Inhibitor Therapy Correct Use ! Treatment Success Patients should be advised that Sexual stimulation is needed Multiple attempts or dosage adjustments may be required Start with recommended dose, then increase or decrease dependent on e(ectiveness and tolerability

•

Sildenafil recommended dose is 50 mg, then increase to 100 mg or decrease to 25 mg

•

Tadalafil and vardenafil recommended dose is 10 mg; increase to 20 mg or decrease to 5 mg as needed

Optimizing PDE5 Inhibitor Therapy Correct Use ! Treatment Success Food interactions

•

Sildenafil and vardenafil may be taken with food but the rate and extent of absorption may be reduced by high"fat foods

•

Tadalafil may be taken with or without food and the rate and extent of absorption is una(ected by high"fat foods

Testosterone augmentation should be prescribed for those with documented hypogonadism Risk"factor modification may improve treatment outcomes Patient education improves success Follow"up visits are essential

Management of ED in Cardiovascular patients

High prevalence of ED in patients with vascular disorders No ED

ED

49! 68!

75! Chronic stable CAD

Acute chest pain

Elevated blood pressure

Kloner RA, Mullin SH, Shook T, et al. Erectile dysfunction in the cardiac patient:how common and should we treat? J Urol. 2003;170#suppl$:S46"S50. Montorsi F, Briganti A, Salonia A, et al. 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. 2003;44:360"365.

Risk Factors of CAD Age Dyslipidemia Smoking Obesity and Sedentary Lifestyle Diabetes mellitus Hypertension Depression Medication

Risk Factors of ED Age Dyslipidemia Smoking Obesity and Sedentary Lifestyle Diabetes mellitus Hypertension Depression Medication

Endothelial Dysfunction is the common dominator Endothelial Dysfunction

Risk Factors

Erectile dysfunction

Cardiovascular disease

Princeton Consensus Panel Cardiovascular risk in patients with erectile dysfunction

Low risk Asymptomatic; < 3 coronary artery disease risk factors, excluding gender Controlled hypertension Mild, stable angina Has had successful coronary revascularization Uncomplicated past myocardial infarction #> 6%8 weeks$ Mild valvular disease Left ventricular dysfunction/congestive heart failure #NYHA class I*$

High risk Unstable or refractory angina Uncontrolled hypertension Left ventricular dysfunction/congestive heart failure #NYHA class III or IV$ Recent myocardial infarction #< 2 weeks$, stroke High"risk arrhythmias Hypertrophic obstructive and other cardiomyopathies Moderate or severe valvular disease

*New York Heart Association functional class

Intermediate risk ) 3 major coronary artery disease risk factors, excluding gender Moderate, stable angina Recent myocardial infarction #> 2 but < 6 weeks$ Left ventricular dysfunction/congestive heart failure #NYHA class II$ Non"cardiac sequelae of atherosclerotic diseases such as stroke or peripheral vascular disease

Low risk Asymptomatic and <3 major risk factors Controlled hypertension Mild, stable angina pectoris After revascularization and without significant residual ischemia Post"myocardial infarction #MI$ #>6%8 weeks$, but asymptomatic. Mild valvular disease Left ventricular dysfunction/congestive heart failure #NYHA class I*$ The Second Princeton Consensus on Sexual Dysfunction and Cardiac Risk: New Guidelines for Sexual Medicine Graham Jackson, Raymond C. Rosen, Robert A. Kloner, John B. Kostis, Journal of Sexual Medicine, Volume 3 Page 28 " January 2006

Intermediate or indeterminate risk Asymptomatic and )3 CAD risk factors #excluding gender$ Moderate, stable angina pectoris MI >2 weeks but <6 weeks LVD/congestive heart failure #NYHA class II$ Non cardiac atherosclerotic sequelae #peripheral

arterial disease, history of stroke, or transient ischemic attacks$

High risk Unstable or refractory angina Uncontrolled hypertension CHF #NYHA class III, IV$ Recent MI #<2 weeks$ High"risk arrhythmia Obstructive hypertrophic cardiomyopathy Moderate to severe valve disease

Management of ED in Cardiovascular patients Princeton Consensus Panel

Sexual Inquiry

Clinical Evaluation

High Risk

Sexual activity deferred until stabilization of cardiac condition

Indeterminate Risk

Cardiovascular assessment and re-stratification

Low Risk

Initiate or resume sexual activity or treatment for sexual dysfunction

Management Recommendations Based on Graded Cardiovascular Risk Assessment Grade of Risk Low risk (60% to 70%)

High Risk (10% to 15%)

Intermediate Risk (15% to 30%)

Management Recommendations Primary care management Consider all first"line therapies Reassess at regular intervals #6"12 m$ Priority referral for specialized cardiovascular management Treatment for sexual dysfunction to be deferred until cardiac condition stabilized; dependent on specialist recommendations Specialized cardiovascular testing #eg, Exercise tolerance testing, echo cardiography$ Re"stratification into high risk or low risk based on the results of cardiovascular assessment

Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and cardiac risk #the Second Princeton Consensus Conference$. Am J Cardiol. 2005;96:313"321

PDE5 Inhibitors Daily use for Erectile Dysfunction

Daily tadalafil Intake Vaginal Penetration#SEP2$

Ability to penetrate partner

12 weeks of treatment Chris McMahon,The Journal of Sexual Medicine. Volume 1 Issue 3 Page 292 " November 2004 SEP = Sexual Encounter Profile diary

Daily tadalafil intake Intercourse Completion #SEP3$

Intercourse completion

Tadalafil 5 mg and 10 mg taken once a day for 12 weeks for the treatment of erectile dysfunction improves patient ability to maintain erection Buvat et al. ESSM. 4"7 December 2005.

Daily tadalafil Intake

Satisfaction with hardness#SEP4$

Satisfaction with hardness

Tadalafil 5 mg and 10 mg taken once a day for the treatment of erectile dysfunction improves patient sexual satisfaction Buvat et al. ESSM. 4"7 December 2005.

Daily tadalafil intake Overall Satisfaction #SEP5$

Overall Sexual Satisfaction

Tadalafil 5 mg and 10 mg taken once a day for the treatment of erectile dysfunction improves patient sexual satisfaction Buvat et al. ESSM. 4"7 December 2005.

112 ED Patients

Improved spontaneous erectile function in men with arteriogenic ED treated with a nightly dose of sildenafil for one year Group 1

50 mg sildenafil nightly One Year

1 m 6 months

Group 2 50 " 100 mg sildenafil on demand

Follow up

Sommer F, Klotz T, Engelmann U. Asian J Androl 2007; 9 #1$: 134"141

Follow up

Nightly

On demand

Sommer F, Klotz T, Engelmann U. Asian J Androl 2007; 9 #1$: 134"141

! of patients with normal EF domain

Improved spontaneous erectile function in men with arteriogenic ED treated with a nightly dose of sildenafil for one year

PSV cm/sec

Improved spontaneous erectile function in men with arteriogenic ED treated with a nightly dose of sildenafil for one year

Patients who maintained normal EF for 6 months Sommer F, Klotz T, Engelmann U. Asian J Androl 2007; 9 #1$: 134"141

Indications for PDE5 Inhibitors daily use Failed on demand use Di'cult to treat Erectile dysfunction #diabetes, after radical prostatectomy$ Honeymoon impotence Rehabilitation after radical prostatectomy

Long"Term Continuous Treatment with Sildenafil Ameliorates Aging"Related Erectile Dysfunction

•

Aging"related erectile dysfunction is characterized by a loss of smooth muscle cells and fibrosis in the corpora cavernosa, and functionally by veno"occlusive dysfunction manifested by inability to maintain rigid erection.

•

PDE5 inhibitors, via upregulating inducible nitric oxide synthase #iNOS$, have anti"fibrotic properties in penile tissues.

Ferrini et al. Published on February 14, 2007 as DOI:10.1095/biolreprod.106.059642

Long"Term Continuous Treatment with Sildenafil Ameliorates Aging"Related Erectile Dysfunction

Aged male rats Untreated young rats Aged male rats #20 month old$ #5 months old$ served #20 month old$ as controls. received sildenafil in received plain water for 45 days their drinking water for 45 days

Response to ICI #mmHg$

Long"Term Continuous Treatment with Sildenafil Ameliorates Aging"Related Erectile Dysfunction

Ferrini et al. Published on February 14, 2007 as DOI:10.1095/biolreprod.106.059642

Drop rate #mmHg/1st min$

Long"Term Continuous Treatment with Sildenafil Ameliorates Aging"Related Erectile Dysfunction

Ferrini et al. Published on February 14, 2007 as DOI:10.1095/biolreprod.106.059642

Long"Term Continuous Treatment with Sildenafil Ameliorates Aging"Related Erectile Dysfunction Young

Old

Old + Sildenafil

Reduced smooth muscle/collagen ratio and increased collagen content in the aged rat corpora cavernosa

Endothelial Repair Endothelial Progenitor Cells

Neovascularization

Endothelial Regeneration Urbich C, Dimmeler S : Endothelial Progenitor Cells Characterization and Role in Vascular Biology. Circ Res. 2004;95:343"353.

EPCs numbers #PC/ml$

Circulating endothelial progenitor cells in subjects with erectile dysfunction

Foresta et al... Int J Impot Res. 2005 May"Jun;17#3$:288"90.

EPCs numbers #PC/ml$

Circulating endothelial progenitor cells in subjects with erectile dysfunction

Foresta et al. Eur Urol. 2007 May;51#5$:1411"9.

E(ect of single vardenafil Administration Vardenafil

EPCs numbers #PC/ml$

Base line

Foresta et al. Eur Urol. 2007 May;51#5$:1411"9.

EPCs numbers #PC/ml$

E(ect of Chronic Tadalafil Administration Controls

ED

20 mg/3 times/W for 3 months Foresta et al Int J Impot Res. 2006 Sep"Oct;18#5$:484"8.

New PDE5 Inhibitors

Udenafil #Zydena$ A newly developed, potent, selective PDE5 inhibitor Pharmacokinetic profiles include a Tmax of 1.0%1.5 hours and a T1/2 of 11% 13 hours, i.e. relatively rapid onset and long duration of action. Selectivity profile of udenafil is similar to that of sildenafil, it does not inhibit PDE11

Avanafil : The Ultra"Short PDE5 Inhibitor Greatest selectivity for PDE5, when compared to other PDE5 inhibitors Avanafil is rapidly absorbed after oral administration, with T max of 35 minutes. A short plasma T 1/2 < than 1.5 hours. • Shorter side e(ects • Twice / day • Shorter duration of drug drug interaction Avanafil plus nitroglycerin resulted in smaller changes in blood pressure and heart rate, a shorter duration of interaction with nitroglycerin, and fewer subjects with clinically significant hypotension than did combined treatment with other PDE5 inhibitors and nitroglycerin.

SLx"2101: The Ultra"Long PDE5 Inhibitor SLx"2101 is a, long acting PDE"5 inhibitor for disorders associated with endothelial dysfunction, including ED Phase IIa study shows that this drug is working at 48 hours after a single dose of 10 mg Unlike the currently approved PDE"5 inhibitors, SLx"2101 is two drugs in one. When first taken, SLx"2101 has a fast action #15 min$. While it is still working, the body metabolize it into a second drug, SLx"2101m1#v long acting 48 hours$.

Second"Line Therapy for Management of ED

Second"Line Therapy for Management of ED Vacuum constriction devices Intracavernosal injection • Alprostadil • Drug mixture #trimix: papaverine, phentolamine, alprostadil$ Transurethral alprostadil #MUSE®$

MUSE®=Medicated Urethral System for Erection.

Second"Line Therapy: VCDs Lack of interest in drug therapy Specific contraindications to drug therapy #e.g. nitrate intake$ Patient preference Vacuum

Second"Line Therapy: Intracavernosal Injection Lack of response to oral therapy Contraindications to specific oral drugs Adverse reactions/intolerance to oral drugs More reliable, instant, predictable erection Patient preference

Second"Line Therapy: Medicated Urethral System for Erection #MUSE$ Lack of response to oral therapy Contraindications to specific oral drugs Adverse reactions/intolerance to oral drugs Rapid, predictable erection

Third"Line Therapy for Management of ED

Third"Line Therapy: Penile Prostheses Intolerance or lack of response to other treatment modalities Irreparably damaged erectile tissue Specific concomitant medical conditions such as vascular or neurologic disease, chronic renal disease, and genital trauma #eg, Peyronie’s disease$

Third"Line Therapy: Penile Revascularization Only performed in carefully selected patients

•

Young men with traumatic pelvic injury or congenital ED

•

Poor response in men with diabetes, neurologic disorders, nicotine abuse

Data over a 10"y period showed an overall long"term success rate of 48!

•

Another 29! reported successful intercourse aided by oral or intracavernosal injection therapy

Combination Therapy for Monotherapy Nonresponders Sildenafil + transurethral alprostadil Sildenafil + triple"agent intracavernosal injection Transurethral alprostadil + VCD or penile prosthesis Sildenafil + psychosocial counseling Sildenafil + testosterone replacement therapy

Advantages of Therapeutic Options Psychosexual therapy

Noninvasive, involves partner, may be curative

PDE5 inhibitors

Oral therapy, e(ective

Transurethral alprostadil

Local therapy, few systemic side e(ects

Intracavernosal alprostadil or drug mixtures

Highly e(ective, few systemic side e(ects

VCDs

Least expensive over time, no systemic side e(ects

Penile prostheses

Highly e(ective

Disadvantages of Therapeutic Options Psychosexual therapy

Time"consuming; patient resistance; variable e'cacy; cost; availability of qualified providers

PDE5 inhibitors

Contraindicated in patients receiving nitrates; interactions with alpha blockers need to be considered; potential for drug" food interactions may delay onset and reduce e'cacy

Transurethral alprostadil

Moderately e(ective; requires o'ce training; causes penile pain; relative cost; partner"related vaginal irritation

Disadvantages of Therapeutic Options Intracavernosal alprostadil or drug mixtures

Requires injection; high dropout rate; can cause priapism, penile fibrosis, or penile pain

VCDs

Unnatural erection; causes petechiae, numbness #20!$, trapped ejaculation

Penile prostheses

Unnatural erection #semi"rigid device$; risk of infection; requires anesthesia/ surgery; replacement in 5"10 years