Tratamento da Disfunção Erétil Masculina GILBERTO DE NUCCI.

Tratamento da Disfunção Erétil Masculina

GILBERTO DE NUCCI

Dúvidas

[email protected]

Site

www.gilbertodenucci.com

Dúvidas

[email protected]

Site

www.gilbertodenucci.com

ANFÍBIOS

• A fertilização é interna nos Urodela (salamandras), mas sem a participação de qualquer estrutura que se assemelhe a um falo. A cloaca do macho e da fêmea são pressionadas uma contra a outra para que ocorra a transferência de esperma, ou o macho deposita um pacote de esperma que é subsequentemente apanhado pela cloaca da fêmea. Salamandra

SQUAMATA• Na ereção, os hemipênises são invertidos, tanto por ação muscular como por ingurgitamento

vascular. Os hemipênises possuem tanto corpos cavernosos como espaços linfáticos.

A - Hemipênis iniciando eversão. B - Hemipênis evertido

A

B

SQUAMATA• Cada hemipênis é funcionalmente um falo

independente do outro. Assim sendo, em cada cópula apenas um hemipênis é introduzido na cloaca da fêmea.

• Na detumescência o hemipênis é invertido pela ação de músculos retratores.

• Na fêmea, um par de hemiclitóris pode estar presente no teto da cauda.

Hemipênises completamente evertidos

RÉPTEIS3. Nos Crocodilia e Chelonia há um falo mediano intracloacal

• Nos quelônios, o falo consiste de um órgão mediano e dorsoventralmente achatado, que repousa na parede ventral da cloaca.

Pênis exposto de tartaruga Chelonoides carbonaria - Posição do falo em repouso na cloaca

Scand J Public Health. 2010 Jul;38(5):445-56. Epub 2010 May 21.

Sexual problems in 18-67-year-old Norwegians.

Traeen B, Stigum H.SourceDepartment of Psychology, University of Tromsø, Tromsø, Norway. [email protected]

AbstractAIM: The aim of this study was to describe and analyse the prevalence of sexual problems in Norway.

METHODS: The results are based on two samples from 2008, one of which was taken from 1671 web interviews in December among persons ranging from 18-67 years of age, and the other being a survey on sexual behaviour among a random sample of 12,000 Norwegians between the ages of 18 and 59, taken in April. Main outcome measures: The prevalence of sexual problems during the past 12 months.

RESULTS: Generalised linear model analyses showed that the highest expected prevalence of manifest problems was found in the following groups: reduced sexual desire problems in 60-67-year-old women with university education (52%); orgasm problems in 18-29-year-old women with less than university education (32%); genital pain in 18-29-year-old women with less than university education (19%); premature ejaculation problems in 18-29-year-old men with less than university education (27%); delayed ejaculation problems in men with less than university education (12%); erectile dysfunction in 60-67-year-old men (34%); and lubrication problems in 60-67-year-old women living in southeast Norway (29%). Sexual problems correlated negatively with sexual wellbeing.

CONCLUSIONS:

This research indicates that sexual problems represent a public health problem.

Definição

A disfunção erétil masculina é a incapacidade em obter ou manter

uma ereção peniana rígida o suficiente para que ocorra

penetração.

A disfunção erétil masculina é a incapacidade em obter ou manter

uma ereção peniana rígida o suficiente para que ocorra

penetração.

N = 1290

48%

17%

25%

10%

Normal Minimal ED Moderate EDComplete ED

Feldman HA et al. J Urol. 1994;151:54-61.

Estudo epidemiológico de DE em Massachusetts

• Prevalência de DE em homens de 40–70 anos.

0

10

20

30

40

50

60

70

4040 5050 6060 7070

Distribuição por Idade (MA)

1290 Homens

%

DE LeveDE Leve DE ModeradaDE Moderada DE CompletaDE Completa

anosanos

Sleep MedicineVolume 11, Issue 10 , Pages 1019-1024, December 2010

Prevalence of erectile dysfunction complaints associated with sleep disturbances in Sao Paulo, Brazil: A population-based survey

Monica L. Andersen, Rogerio Santos-Silva, Lia R.A. Bittencourt, Sergio Tufik

Received 22 February 2009; received in revised form 28 July 2009; accepted 21 August 2009.

Abstract Introduction: The aims of this study were to estimate the prevalence of erectile dysfunction (ED) complaints in a population-based sample from Sao Paulo and to determine the associations of ED prevalence with sleep disturbances, testosterone levels, age, body mass index (BMI), socioeconomic factors and selected medical history indicators. Methods: The Epidemiologic Sleep Study (EPISONO) is a population-based study of sleep and risk factors for sleep disturbances in Brazil’s largest city, Sao Paolo. This study adopted a probabilistic three-stage cluster sampling approach for the city of Sao Paulo. Questionnaires that covered medical conditions and sexual and erection complaints were administered and polysomnographies and fasting blood samples were collected. The patient cohort of the current study of ED consisted of 467 men, aged 20–80years at the time of their enrollment in EPISONO. The percentage of men who participated in EPISONO but refused to participate in our study was 2.3%. Results: The prevalence of ED complaints in the study

cohort was 17.08% overall. ED complaints ranged from 7.3% in younger men (20–29years old) to 63.25% in older men (>50years old) (adjusted odds ratio [OR]=21.65). The logistic regression model showed that both reduced time spent in REM sleep and fragmented sleep had significant effects as risk factors for ED complaints. Obesity (OR=1.8), low testosterone levels (OR=4.28), low quality of life (OR=4.4), an apnea–hypopnea index over 15 (OR=2.75), and obstructive sleep apnea syndrome (OR=2.13) were also significantly associated with a higher risk of ED complaints. Conclusion: EPISONO study indicates that ED complaints are relatively common phenomena, especially among older men. Adequate sleep patterns and normal or high levels of testosterone, which serve as markers for sexual motivation, may be protective against ED. The prevalence of sleep apnea showed a strong impact on erectile function and subsequently negatively affects sexual activity.

Beneficial effects of extendedrelease doxazosin and doxazosin standard on sexual health - BJUINTERNATIONAL |97, 559 – 566 1

The incidence of concomitant hypertension and ED with advancing age

Incidence of hypertension and ED, %Age, years

56-65 51.4

66-75 62.3

76-85 67.2

86 68,4

CA CC

Cross-section of the penile distal shaft from human, Cavernosal artery (CA) Corpus cavernosum (CC)

InternalInternalpudendal a.pudendal a.

Bulbar a.Bulbar a.Urethral a.Urethral a.

C. spongiosumC. spongiosum

Cavernous a.Cavernous a.

Arterial SupplyArterial Supply

C. cavernosum C. cavernosum

Dorsal a.Dorsal a.

Venous drainageVenous drainage

Cavernous v.Cavernous v.

C.cavernous v.C.cavernous v.

PrepostaticPrepostaticplexusplexus

InternalInternalpudendal v.pudendal v.Bulbar v.Bulbar v.

Urethral v.Urethral v.

C. spongiosumC. spongiosum

Superficial dorsal v.Superficial dorsal v.

Deep dorsal v.Deep dorsal v.

Circumflex v.’sCircumflex v.’s

Flaccid StateFlaccid State

Emissary v.Emissary v.

Tunica albugineaTunica albuginea

Erect stateErect state

Penile ErectionPenile Erection

2525

00

200200

100100

00

Pu

d. A

.P

ud

. A.

(m

l/m

in)

(ml/

min

)I.

C.

I.C

. (

cm H

(cm

H22O

)O

)

Cavernous nerveCavernous nerve

Pudendal nervePudendal nerve

1 2 3 41 2 3 4 3 3 5 6 5 6 7 7

Causas conhecidas de DE• Depressão

• Ansiedade

• Doença vascular (arterial ou venosa)

• Fatores hormonais

• Doença autonômica

• Uso de Medicamentos

• Trauma (fratura)

• Doenças Penianas (Peyronie)

Doppler evaluation of erectile dysfunction – Part 2 - International Journal of Impotence Research (2006), 1–6

a

Male (24 years old) with fracture of the penis. Following sexual activity, the patient presented with loss of penile rigidity, pain, hematoma of the penile shaft and hematuria. (a) Retrograde

urethrogram reveals associated rupture of the bulbar urethra (arrow). The patient subsequently underwent surgical exploration and repair

http://images.suite101.com/1490270_com_peyronies.jpg

Erectile Dysfunction - THE JOURNAL OF UROLOGY

Percent distribution of organic causes of ED

Erectile Dysfunction - THE JOURNAL OF UROLOGY - Vol. 175, S25-S31, March 2006

Beneficial effects of extendedrelease doxazosin and doxazosin standard on sexual health - BJUINTERNATIONAL |97, 559 – 566 1

Regulação PeriféricaRegulação Periférica

1. Mediadores Contráteis1. Mediadores Contráteis

Noradrenalina (NA)Noradrenalina (NA)

Rho ARho A

Endotelina-1 (ET-1)Endotelina-1 (ET-1)

Prostaglandina FProstaglandina F22 (PGF(PGF22))

Tromboxano ATromboxano A22 (TXA (TXA22))

Angiotensina IIAngiotensina II


1. Mediadores Contráteis1. Mediadores Contráteis

Noradrenalina (NA) – até o momento, o único que Noradrenalina (NA) – até o momento, o único que

aparentemente é clinicamente relevante, visto o uso aparentemente é clinicamente relevante, visto o uso

terapêutico de bloqueadores adrenérgicos terapêutico de bloqueadores adrenérgicos

(fenoxibenzamina intra-cavernosa, fentolamina (fenoxibenzamina intra-cavernosa, fentolamina

por via intra-cavernosa e via oral).por via intra-cavernosa e via oral).

RhoA-GDP

RhoA-GTP

Rho-Kinase

Phosphatase phosphatase (?)

MLC Phosphatase (Active)

MLC Phosphatase~P (Inactive)

MLCSM: RelaxedPenis: Erect

MLC-PSM: ContractedPenis: Not Erect

MLC kinase

Calmodulin-Ca2+

[Ca2+]i

The state of myosin light chain (MLC) phosphorylation in cavernosal smooth muscle (SM) is regulated by MLC kinase and MLC phosphatase.

Inh

ibit

ion

of

Ton

ic C

ontr

acti

on—

A N

ovel

Way

to

Ap

pro

ach

Ere

ctil

e D

ysfu

nct

ion

? -

Jour

nal o

f A

ndro

logy

, Vol

. 23,

No.

5,

Concentration-response curve to phenylephrine (PE) in C. durissus (snake) aorta in control conditions and treated with the

Rho-kinase inhibitor Y-27632 (10 μM)

Peripheral RegulationPeripheral Regulation

1. Contractant Factors1. Contractant Factors Noradrenaline

Rho A

Endotelin-1 (ET-1)

Prostaglandin F2 (PGF2)

Tromboxane A2 (TXA2)

Angiotensin II

Erectile function in anesthetized dog after intracavernous administration of losartan

Journal of Urology, 157, 1997


2. Mediadores Relaxantes2. Mediadores Relaxantes Óxido Nítrico (NO)Óxido Nítrico (NO) Acetilcolina (ACh)Acetilcolina (ACh) NeuropeptídeosNeuropeptídeos (VIP, CGRP)(VIP, CGRP) Prostanóides (PGEProstanóides (PGE11))

HistaminaHistamina ATP / adenosinaATP / adenosina H2S e SO2H2S e SO2

NO-cGMP BiochemistryNO-cGMP Biochemistry

L-NAMEL-NAME

NOSNOS

ARGININEARGININE NONO

SGCSGC

cGMPcGMP

GTPGTP

PDEPDE-5-5

(-)

(-)

ViagraViagra

GMPGMP

NO mediates relaxation of HCCNO mediates relaxation of HCC

4 2 4 8 164 2 4 8 16

WW

WW

WW1 g1 g

2 min2 min

HzHz

PEPE

NAANAA

4 2 4 8 164 2 4 8 16

L-ARGL-ARG

4 2 4 8 164 2 4 8 16

The New England J. of Medicine, 326, 1992The New England J. of Medicine, 326, 1992

SNAP relaxes HCCSNAP relaxes HCC

4 2 4 8 164 2 4 8 16

-5.5-5.51 g1 g

2 min2 min

HzHz

PEPE

-6-6

-6.5-6.5

-7-7-7.5-7.5-8-8


Effect of M&B on HCC relaxationEffect of M&B on HCC relaxation

4 2 4 8 164 2 4 8 16 4 2 4 8 16 4 2 4 8 16

WW

WW

WW1 g1 g

2 min2 min

HzHz

PEPE

M&BM&B


PNAS, 97, 2000

NO-cGMP BiochemistryNO-cGMP Biochemistry

L-NAMEL-NAME

NOSNOS

ARGININEARGININE NONO

SGCSGC

cGMPcGMP

GTPGTP

PDEPDE-5-5

(-)

(-)

ViagraViagra

GMPGMP

N

NH

O

O S

CH3

NN

CH3

O O

N

N

CH3

CH3

N

NH

O

O S

CH3

O O

N

N

CH3

CH3

N

N

CH2

CH3

NH

OO

N

N

O

OCH3

Sildenafil (Viagra ™)Sildenafil (Viagra ™)

Tadalafil (CialisTadalafil (Cialis ™ ™))

Vardenafil (LevitraVardenafil (Levitra ™ ™))

Structures of PDE5 InhibitorsStructures of PDE5 Inhibitors

Lodenafil carbonate (HellevaLodenafil carbonate (Helleva ™ ™))

Eur J Pharmacol. 2008 Sep 4;591(1-3):189-95. Epub 2008 Jun 19.

Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum.

Toque HA, Teixeira CE, Lorenzetti R, Okuyama CE, Antunes E, De Nucci G.Department of Pharmacology, UNICAMP, Campinas, SP, 13081-970, Brazil.

Abstract

Nitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed (0.001-100 microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 microM) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in PDE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate.

Pharmacological management of Pharmacological management of ED (I)ED (I)

• Orally active inhibitor of PDE5;Orally active inhibitor of PDE5;

• Promotes erection by inhibiting the Promotes erection by inhibiting the

degradation of cGMP;degradation of cGMP;

• Dosage: 25, 50 or 100 mg;Dosage: 25, 50 or 100 mg;

• Erectogenic effect is achieved following Erectogenic effect is achieved following

sexual stimulation;sexual stimulation;

• TTmaxmax: 1 h after administration;: 1 h after administration;

• TT1/21/2: 4-5 h.: 4-5 h.

• Orally active inhibitor of PDE5;Orally active inhibitor of PDE5;

• Promotes erection by inhibiting the Promotes erection by inhibiting the

degradation of cGMP;degradation of cGMP;

• Dosage: 25, 50 or 100 mg;Dosage: 25, 50 or 100 mg;

• Erectogenic effect is achieved following Erectogenic effect is achieved following

sexual stimulation;sexual stimulation;


• TT1/21/2: 4-5 h.: 4-5 h.

N

NH

O

O S

CH3

NN

CH3

O O

N

N

CH3

CH3

SildenafilSildenafil

Pharmacological management of Pharmacological management of ED (II)ED (II)

• Novel inhibitor of PDE5;Novel inhibitor of PDE5;

• Dosage: 5, 10, 20 or 40 mg;Dosage: 5, 10, 20 or 40 mg;

• Potency and selectivity somewhat superior Potency and selectivity somewhat superior

to sildenafil;to sildenafil;

• TTmaxmax: 0.7-0.9 h after administration;: 0.7-0.9 h after administration;

• TT1/21/2: 4-5 h.: 4-5 h.

• Novel inhibitor of PDE5;Novel inhibitor of PDE5;


• Potency and selectivity somewhat superior Potency and selectivity somewhat superior

to sildenafil;to sildenafil;

• TTmaxmax: 0.7-0.9 h after administration;: 0.7-0.9 h after administration;

• TT1/21/2: 4-5 h.: 4-5 h.

N

NH

O

O S

CH3

O O

N

N

CH3

CH3

N

N

CH2

CH3

VardenafilVardenafil

Pharmacological management of ED (III)Pharmacological management of ED (III)



• TT1/21/2: 17.5 h;: 17.5 h;

• Long half-life has been associated with an erectogenic Long half-life has been associated with an erectogenic

potential of the drug lasting for 24 h.potential of the drug lasting for 24 h.



• TT1/21/2: 17.5 h;: 17.5 h;

• Long half-life has been associated with an erectogenic Long half-life has been associated with an erectogenic

potential of the drug lasting for 24 h.potential of the drug lasting for 24 h.

NH

OO

N

N

O

OCH3

TadalafilTadalafil

Erectile Dysfunction - THE JOURNAL OF UROLOGY

PDE-5 inhibitor efficacy in successful intercourse. Adapted from Padma-Nathan,54 Brock55 and Porst56 et al.

Summary of the key pharmacokinetic data forthe three PDE5 inhibitors

EA

U G

uid

elin

es

on

Ere

ctile

Dysf

un

ctio

n:

An

Up

date

- e

uro

pean

uro

log

y 4

9

(20

06

) 8

06

–81

5

Common adverse events of the three PDE5 inhibitors

EAU Guidelines on Erectile Dysfunction: An Update - european urology 49 (2006) 806–815

Selectivity ratio = PDE5/PDEx potency Sildenafil Tadalafil Vardenafil

(a) PDE5 1 1 1

(b) PDE6 10 780 224

(c) PDE11 346 5.5 203

Comparative profile of currently available PDE5 inhibitors.

Alfa-bloqueadores são considerados a monoterapia mais efetiva para LUTS causada por HBP.

Inibidores de PDE-5 são considerados a monoterapia mais efetiva para DE.

LUTS e DE são altamente prevalente em homens > 50 anos

Changes in supine and standing blood pressure, expressed as maximum differences from placebo, following co-administration of a single dose of tadalafil 20 mg (maximum therapeutic dose) with

alfuzosin 10 mg once daily [10], doxazosin 0.8 mg once daily [9] or tamsulosin 0.4 mg once daily [9]. *Statistically significantly different from placebo (i.e. 95% confidence interval did not contain 0).

BP, blood pressure

Lower urinary tract symptoms and sexual dysfunction: a common approach - J O U R N A L C O M P I L A T I O N© 2 0 0 8 B J U I N T E R N A T I O N A L | 101 , S U P P L E M E N T 3 , 2 2 – 2 6 – fig 01

Impact of alfuzosin 10 mg once daily administered over 3 years on sexual function assessed using the Danish Prostate Symptom Score sexual function domain (DAN-PSSsex) in 689 men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia [22]. The DAN-PSSsex assesses the severity and bother of 3 sexual

symptoms: stiffness of erection, volume of ejaculate and pain/discomfort at ejaculation. For men experiencing a given sexual symptom, a weighted score (rated 0 to 9) is calculated by multiplying the symptom score (0–3) by the

bother score (0–3). For each sexual symptom, lower values indicate better function/satisfaction.


Impact of alfuzosin 10 mg once daily, sildenafil 25 mg once daily or the combination of both onInternational Prostate Symptom Score (IPSS) and International Index of Erectile Dysfunction (IIEF) [31]. © 2007. Reprinted with permission from Elsevier. For IPSS, lower scores indicate improvement.

For IIEF, higher scores indicate better function.


NO-cGMP Biochemistry

L-NAMEL-NAME

NOSNOS

L-ARGININEL-ARGININE NONO

sGCsGC

cGMPcGMP

GTPGTP

PDE5PDE5

(-)

(-)

PDE5PDE5inhibitorsinhibitors

5’GMP5’GMP

ODQODQ(-)

-8 -7 -6 -5

0

40

80

120

log [Drug] (M)R

elax

atio

n (

%)

pECpEC5050 EEmaxmax

6.71 6.71 0.05 0.05 111 111 5 5

6.85 6.85 0.06 0.06 117 117 5 5

N

NH

O

O S

CH3

NN

CH3

O O

N

N

CH3

CH3

SildenafilSildenafil(MW 474.46)(MW 474.46)

N

N

N

F

N N

NH2

BAY 41-2272BAY 41-2272(MW 360.40)(MW 360.40)

BAY 41-2272 induces HCC relaxationBAY 41-2272 induces HCC relaxationBAY 41-2272 induces HCC relaxationBAY 41-2272 induces HCC relaxation

GCs reduzida

GCs ativada

GCs oxidada

Ativadores GCs:BAY 60-2770BAY 58-2667

ODQERO

NADPH oxidase

Estimuladores GCs:

BAY 41-2272

Equilíbrio redox GCs

Oxidação

GCs ativada

NO

NO

H.H.H.W. Schmidt et al., 2009

Curr Pharm Des. 2010 May;16(14):1619-33.

Exploring the potential of NO-independent stimulators and activators of soluble guanylate cyclase for the medical treatment of erectile dysfunction.Gur S, Kadowitz PJ, Hellstrom WJ.

Department of Urology and Pharmacology, Health Sciences Center, Tulane University, 1430 Tulane Avenue, New Orleans, LA 70112, USA.

AbstractNitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the receptor that catalyzes the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP). Binding of the physiological activator, NO, to the reduced heme moiety of sGC increases the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP) and engages crucial effector systems such as protein kinases, phosphodiesterases, and ion channels. The development of compounds that activate sGC independent of NO release has therapeutic implications. Recent studies have demonstrated the potential use of heme-dependent sGC stimulators (e.g. YC-1, BAY 41-2272, BAY 41-8543, BAY 63-2521, CFM-1571 and A-350619) and heme-independent sGC activators (e.g. BAY 58-2667, HMR-1766, S-3448, A-778935) in the treatment of cardiovascular diseases. Erectile dysfunction (ED) affects millions of men. Phosphodiesterase (PDE)-5 inhibitors, produce an NO-dependent increase in intracellular cGMP concentration, have been a successful approach in the treatment of ED. However, >30% of men with ED do not respond to PDE-5 inhibitor therapy, implying that endogenous NO production may be impaired to such an extent that inhibition of cGMP degradation produces no significant therapeutic advantage. Endogenous NO released from nitrergic nerves in the corpora cavernosa is significantly decreased in various conditions (e.g. diabetes, aging, and hypertension) and have reduced activation of the NO-sGC-cGMP pathway. It is conceivable that sGC stimulators and/or activators may be more effective than PDE5 inhibitors in the treatment of ED in such circumstances by improving NO-sGC-cGMP signaling and erectile function. This novel drug therapy approach for the treatment of ED shows promise.

O sistema NO-cGMP-PDE5 é importante O sistema NO-cGMP-PDE5 é importante para a ereção penianapara a ereção peniana

Conclusão

Crotalus durissus terrificus

Effect of L-NAME in phenylephrine induced contraction in corpus cavernosum from tortoise and mice

TortoiseChelonoidis carbonaria (n=1)

MiceC57BL/6

CONCLUSÃOO sistema NO-cGMP-PDE5 de relaxamento do corpo cavernoso está presente desde o

aparecimento do pênis primário em répteis.

Príapo, Deus grego da fertilidade.

http://upload.wikimedia.org/wikipedia/commons/7/76/Mercury_god.jpg

Tratamento da Disfunção Erétil Masculina GILBERTO DE NUCCI.

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