Committee 14

Pharmacotherapy for Erectile DysfunctionChairs

H. PADMA-NATHAN (USA),

G.CHRIST (USA)

MEMBERS

G.ADAIKAN (SINGAPORE),

E. BECHER (ARGENTINA),

G. BROCK (CANADA),

S. CARRIER (CANADA),

C. CARSON (USA),

J. CORBIN (USA),

S. FRANCIS (USA),

R. DEBUSK (USA),

I. EARDLEY (U.K.),

H. HEDLUND (NORWAY),

A. HUTTER (USA),

G. JACKSON (U.K.),

R. KLONER (USA),

C. LIN (USA),

K. MCVARY (USA),

A. MCCULLOUGH (USA),

A. NEHRA (USA),

H. PORST (GERMANY),

C. SCHULMAN (BELGIUM),

A. SEFTEL (USA),

I. SHARLIP (USA),

C. STIEF (GERMANY),

C. TELOKEN (BRAZIL)

503

CHAPTER 15

IV. HIGH AND INTERMEDIATELEVEL OF EVIDENCE CARDIO

VASCULAR PUBLICATIONS IN THEFIELD OF ED PHARMACO-THERAPY

(graded by cardiologists on committeee)

III. LOCAL ED THERAPIES

II. ORAL ED PHARMACOTHERAPIES

I. INTRODUCTION

B. EVIDENCE-BASED REVIEWOF ED PHARMCOTHERAPIES

4.V. TOPICAL NITROGLYCERIN

4.IV. TOPICAL PAPAVERINE

4.III. TOPICAL MINOXIDIL

4.II. TOPICAL PGE1

4.I. TOPICAL THERAPY FORERECTILE DYSFUNCTION –

BACKGROUND

GENERAL PRINCIPLES OFTOPICAL AGENTS

TOPICAL THERAPIES 4.

3.VI. COMBINATIONS

3.V. PAPAVERINE

3.IV. ALPROSTADIL (PGE1)

3.III. L-ARGININE

3.II. VASOACTIVE INTESTINALPOLYPEPTIDE

3.I. PDE 5 INHIBITORS

PERIPHERALLYACTIVE

3.

2.II. PHENTOLAMINE

2.I. YOHIMBINE

CENTRALLY AND PER-IPHERALLY ACTIVE

2.

1.VI. NALTREXONE

1.V. NALMEFENE

1.IV. DELEQUAMINE

1.III. TRAZODONE

1.II. MELANOCORTIN AGONIST:MELANOTAN II and PT-141

1.I. APOMORPHINE

CENTRALLY ACTINGDRUGS

1.

I. INTRODUCTION

A. MECHANISM OF ACTIONAND BASIC SCIENCE OF ED

PHARMACOTHERAPIES

504

CONTENTS

As is clear from the other chapters in this compendium, incredible advances have been made in the understan-ding, diagnosis and treatment of sexual dysfunction/disorders. In the case of erectile dysfunction, this has ledto an improved understanding of the molecular and cellular mechanisms of action of nearly all of the current-ly used drug therapies. In the sections that follow, the basic research underlying the putative mechanism ofaction (MOA) of the available centrally and peripherally acting drugs is reviewed.

These reviews are accompanied by two summary figures (Figures 1, 2), that provide a conceptual frameworkfor understanding this field of medical therapy. In addition, a detailed summary table (Table 1) is given, whichoutlines as much as possible, the specific MOA of these drugs. In the last MOA section, which deals with theexciting developments in the PDE5 field, there are three additional figures (Figs. 3-5) and an additional Table(Table 2), to provide an exquisite level of detail about the currently most explosive area of drug research anddevelopment in erectile dysfunction.

We hope this material will assist the interested physician/health care provider in better understanding theactions of currently available drugs, and in better educating their patients about the same.

INTRODUCTION

A. MECHANISM OF ACTION AND BASIC SCIENCE OF ED PHARMACOTHERAPIES

505

Pharmacotherapy for Erectile DysfunctionH. PADMA-NATHAN , G.CHRIST

G.ADAIKAN, E. BECHER, G. BROCK, S. CARRIER, C. CARSON, J. CORBIN, S. FRANCIS, R. DEBUSK, I. EARDLEY, H. HEDLUND, A. HUTTER, G. JACKSON, R. KLONER, C. LIN,

K. MCVARY, A. MCCULLOUGH, A. NEHRA, H. PORST, C. SCHULMAN, A. SEFTEL, I. SHARLIP, C. STIEF, C. TELOKEN

506

Fig

ure

1 :

Sche

mat

ic d

epic

tion

of th

e ge

nera

l cla

ssif

icat

ion

and

puta

tive

site

s of

act

ion

of th

e cu

rren

tly u

sed

drug

s fo

r th

e tr

eatm

ent o

f er

ectil

e dy

sfun

ctio

n.

507

Fig

ure

2 :

Sche

mat

ic d

iagr

am s

how

ing

the

mec

hani

sm o

f ac

tion

and

impa

ct o

f cu

rren

tly u

sed

drug

s at

the

leve

l of

the

corp

oral

sm

ooth

mus

cle

cell.

+:

deno

tes

stim

ulat

ory

path

way

,an

d -:

den

otes

inh

ibito

ry p

athw

ay. W

here

PK

A,

PK

C a

nd P

KG

den

ote

prot

ein

kina

ses

A,

C a

nd G

res

pect

ivel

y, D

AG

den

otes

dia

cyl

glyc

erol

, M

LC

20 d

enot

es m

yosi

n lig

ht c

hain

,SM

PP

deno

tes

smoo

th m

uscl

e m

yosi

n ph

osph

atas

e, C

am d

enot

es c

alm

odul

in, M

LC

K d

enot

es m

yosi

n lig

ht c

hain

kin

ase,

Rho

Ade

note

s R

ho A

kina

se, a

nd G

q an

d G

s de

note

the

Gpr

otei

n co

uple

d to

act

ivat

ion

of P

hosp

holip

ase

C a

nd a

deny

late

cyc

lase

enz

ymes

, res

pect

ivel

y.

508

Tabl

e 1

: M

echa

nism

of

actio

n su

mm

ary

(L

egen

d: I

C:

Intr

acav

erno

sal;

IU

: In

taur

ethr

al;

EP

: P

rost

agla

ndin

rec

epto

r; V

IP:

vaso

activ

e in

test

inal

pol

ypep

tide;

NT

G:

nitr

ogly

ceri

ne)

Although the mechanisms underlying erectile func-tion are not fully understood, advances have beenmade regarding the interplay of central and periphe-ral mechanisms. It is now widely agreed that centraldisinhibition plays a crucial role in the induction oferectile responses and this has led to the develop-ment of the central enhancer, the dopaminergic sub-stance apomorphine. Apomorphine acts in the para-ventricular nucleus of the hypothalamus as a dopa-mine (D2) receptor agonist. It works as a pro-erecti-le conditioner at this level to increase the responsesof the erectile pathway following appropriate sexualstimulation. Certainly, understanding the role of cen-tral pathways/mechanisms in the control of the erec-tile process is critical to elucidating the mechanismof action of this newer class of orally active erecto-genic agents. Chapters 10 & 11 in this volume dealsin great detail with this subject, and thus, only a briefsummary is given below.

Physiological erections are initiated, in large part, bycentral stimuli. Depending on the type of stimulus,various areas of the cortex are involved like the occi-pital region for visual, the rhinencephalic for olfacto-ry, the thalamic for tactile and the limbic region forimaginative stimuli. There is good evidence that theseand other stimuli from higher centers are sendinginputs to hypothalamic nuclei (medial preoptic area(MPOA), paraventricular nucleus (PVN)). TheMPOA contains a high density of neurons thatconcentrate androgens and shows an extensive inter-connection to the limbic system and the lower autono-mic brain stem nuclei. The role of the MPOA is torecognise sensory stimuli from the higher braincentres and integrate them with sexual motivation andcopulatory motor programmes. The MPOA plays animportant role in the erectile response, and both phar-macological and electrical stimulation of the MPOAresults in erection in anaesthetised rats (Giuliano et al.,1997: Sato & Christ, 2000; Sato et al., 2001). TheMPOA is also involved in maternal behaviour(Numan, 1988) thermoregulation (Kanosue et al.,1994) and thirst (Bourque et al., 1994).

The PVN also seems to integrate the input from highercenters (Melis & Argiolas, 2002; Melis et al., 2003)

and contains premotor neurones that project directlyonto spinal autonomic preganglionic neurones. ThePVN plays a key role in the erectile response andpharmacological or electrical stimulation of this smallhypothalamic nuclei results in seminal discharge inunanaesthetised rats (Eaton, 1991) and erection andejaculation in anaesthetised rats (Chen et al., 1997).Dopaminergic neurones belonging to the incertohypo-thalamic dopamine system are the main componentsof the PVN. These dopaminergic neurones impinge onoxytocin containing neurones (Bujis et al., 1984). ThePVN is believed to be the nucleus where apomorphi-ne acts as a dopaminergic substance. From the PVN,signals are then transmitted to the brainstem nuclei(periaqueductal grey (PAG), nucleus paragigantocel-lularis (nPGi) and raphe nuclei) and then to the per-iphery of the erectile axis (Marson & McKenna, 1990,1992; Sancila et al., 2002).

Dopamine is one among a number of important cen-tral neurotransmitters involved in the initiation oferection. Dopamine is the main transmitter within thePVN (Eaton, 1991; Allard et al., 2002) that, as discus-sed above, plays an important role in the centralcontrol of erection. Dopamine receptors are dividedinto two main families D1 and D2-like receptors thatare in turn further subdivided into D1 to D5 receptorsubtypes. Apomorphine has a higher affinity for theD2-like receptors (Rampin et al., 2003) that arethought to be the main site for the induction of erec-tions in the PVN (Chen et al., 1999) Apomorphine istherefore postulated to increase erectile responses byacting as a conditioner in the PVN, increasing the res-ponse to sexual stimuli resulting in enhanced erectionsinduced in the periphery (Brien et al., 2002).

In summary, apomorphine is an agonist of the D1-and D2-receptor subtypes that are mainly located inthe paraventricular nucleus of the hypothalamus.Oxytocinergic neurons in this nucleus are responsiveto the administration of apomorphine via activationof both the D1-and D2-receptor subtypes, which sub-sequently induces a cascade of events that reach theperiphery to elicit penile erection. It has been sug-gested that nitric oxide acts as a cofactor at the levelof the paraventricular nucleus of the hypothalamuswith regards to the activation of the oxytocinergicneurons (Melis & Argiolas, 1996). In this scenario,the presence of nitric oxide is thus mandatory inorder to allow for the action of apomorphine. Apo-moprhine SL has recently been approved for marke-ting in Europe at the doses of 2 and 3 mg. The erec-togenic effects are usually seen within 20 minutes ofits administration; provided the presence of an ade-quate sexual stimulation.

1.I. APOMORPHINE

CENTRALLY ACTINGDRUGS

1.

509

Allard, J., Bernabe, J., Derdinger, F., Alexandre, L., McKen-na, K. & Giuliano, F.: Selegiline enhances erectile activityinduced by dopamine injection in the paraventricular nucleusof the hypothalamus in anesthestized rats. Int. J. ImpotenceRes. 14: 518-522, 2002.

Bourque,C.W., Oliet,S.H. & Richard,D. Osmoreceptors,osmoreception, and osmoregulation. Front Neuroendocrinol.15, 231-274 (1994).

Brien, S.E., Smallegange, B., Gofton, WT., Heaton, JPW. AndAdams, MA: Development of a rat model of sexual perfor-mance anxiety: effect of behavioural and pharmacologicalhyperadrenergic stimulation on APO-induced erections. Int.J. of Impotence Res. V.14 P.107-115 2002

Buijs,R.M., Geffard,M., Pool,C.W. & Hoorneman,E.M. Thedopaminergic innervation of the supraoptic and paraventricu-lar nucleus. A light and electron microscopical study. BrainRes. 323, 65-72 (1984).

Chen,K.K., Chan,J.Y. & Chang,L.S. Dopaminergic neuro-transmission at the paraventricular nucleus of hypothalamusin central regulation of penile erection in the rat. J. Urol. 162,237-242 (1999).

Chen,K.K., Chan,S.H., Chang,L.S. & Chan,J.Y. Participationof paraventricular nucleus of hypothalamus in central regula-tion of penile erection in the rat. J. Urol. 158, 238-244 (1997).

Eaton, R.C. et al.: D2 receptors in the paraventricular nucleusregulate genital responses and copulation in male rats. Phar-macol. Biochem. Behav. 39, 177-181 (1991).

Giuliano, F., Bernabe, J., Brown, K, Drouphy, S., Benoit, G.& Rampin, O.: Erectile response to hypothalamic stimulationin rats: role of peripheral nerves. Am. J. Physiol. 273: R1990-R1997, 1997.

Kanosue,K., Zhang,Y.H., Yanase-Fujiwara,M. & Hosono,T.Hypothalamic network for thermoregulatory shivering. Am.J. Physiol 267, R275-R282 (1994).

Marson,L. & McKenna,K.E. A role for 5-hydroxytryptaminein descending inhibition of spinal sexual reflexes. Exp. BrainRes. 88, 313-320 (1992).

Marson,L. & McKenna,K.E. The identification of a brainstemsite controlling spinal sexual reflexes in male rats. Brain Res.515, 303-308 (1990).

Melis, M.R., Succu, S. & Argiolas, A.: Dopamine agonistsincrease nitric oxide production in the paraventricular nucleusof the hypothalamus: correlation with penile erection. Eur. J.Neurosci. 8: 2056-2063, 1996.

Melis, M.R., Argiolas, A.: Reduction of drug-induced yaw-ning and penile erection and of noncontact erections in malerats by the activation of GABAA receptors in the paraventri-cular nucleus: involvement of nitric oxide Eur. J. Neurosci.,15: 852-860, 2002.

Melis. M.R., Succu, S., Mascia, M.S., Cortis, L., Argiolas, A.:Extra-cellular dopamine increases in the paraventricularnucleus of male rats during sexual activity. Eur. J. Neurosci.17: 1266-1272, 2003.

Numan, M.: Neural basis of maternal behavior in the rat. Psy-choneuroendocrinology, 13: 47-62, 1988.

Rampin, O., Jerome, N., Suaudeau, C.: Proerectile effects ofapomorphine in mice. Life Sci., 72: 2329-2336, 2003.

Sancila, M., Giuliano, F., Rampin, O., Mailly, P., Brisorgueil,MJ., Calas, A., Verge, D.: Evidence for a direct projectionfrom the paraventricular nucleus of the hypothalamus to puta-tive serotoninergic neurons of the nucleus paragigantocellula-ris involved in the control of erection in rats. Eur. J. Neuros-ci. 16: 1240-1248, 2002.

Sato, Y. & Christ, G.J.: Differential intracavernous pressure(ICP) responses elicited by electrical stimulation of themedial preoptic area (MPOA). Am. J. Physiol. 268: H964-H970, 2000.

Sato, Y., Zhao, W., & Christ, G.J.: Central modulation of theNO/cGMP pathway affects the MPOA-Induced intracaver-nous pressure (ICP) response. Am. J. Physiol. 281: R269-R278, 2001.

Melanotan II is a synthetic nonselective analog of α-melanocyte–stimulating hormone (α-MSH). α-MSHand adrenocorticotrophin, known as the melanocor-tins, are derived from proteolytic cleavage of the pre-cursor, pro-opiomelanocortin. Melanocortins areimplicated in the regulation of sexual behaviourincluding penile erection, sexual motivation and inthe female rat the secretion of sexual attractants fromthe preputial gland (Thody AJ et al, 1981, van derKraan et al, 1998). Through cloning techniques fivetypes of melanocortin receptors (MC1, MC2, MC3,MC4, and MC5) have been characterized (Wikberget al, 2000).

Injection of α-MSH into the rat hypothalamic per-iventricular region induces grooming, stretching,yawning and penile erection. Grooming, stretchingand yawning but not penile erection seem to bemediated by MC4 receptors which are found almostexclusively in the central nervous system especiallyin the hypothalamus of the rat (Vergoni et al, 1998;Argiolas et al, 2000). A significant central role forthe MC3/MC4 receptor subtypes in modulating theMelanotan II-induced intracorporal pressureincreases in the rabbit has been documented (Vemu-lapalli et al., 2001). Another recent study (Van derPloeg et al., 2002) has provided strong support for anMC4-receptor-mediated proerectile response in spi-nal cord erectile centers, as well as at the level of thesomatosensory afferent nerve terminals in the mousepenis. Moreover, a similar distribution of the MC4receptor subtype has been found in the correspon-ding rat and human tissues. Therefore, while themelanocortin receptor subtype(s) that mediate theproerectile effects of Melanotan II/melanocortins

1.II. MELANOCORTIN AGONIST:MELANOTAN II and PT-141

REFERENCES

510

have not been unequivocally identified, a role for theMC3/MC4 receptors seems likely.

Melanotan II delivered subcutaneously has beenreported to initiate penile erection in normal men aswell as men with psychogenic and organic ED (Dorret al, 1996; Wessells et al, 1998, 2000). It is alsonoted to significantly increase sexual desire (Wes-sells et al, 2000). The frequent side effects associatedwith melanotan II administration are nausea andstretching/yawning.

Trazodone, a serotonin reuptake inhibitor, is a non-tricyclic antidepressant that has been associated withprolonged erection and priapism when administeredorally in depressive patients.

In healthy volunteers trazodone dose dependentlyincreased NPT following REM related erections andblocked the detumescence phase of erection, whichis under sympathetic control, thereby prolonging theerection (Saenz de Tejada et al, 1991). In vitro, tra-zodone attenuated human corporal muscle contrac-tion elicited by both electrical stimulation of adre-nergic nerves and exogenous noradrenaline (Adaikan& Ratnam, 1988; Saenz de Tejada et al, 1991). Com-petitive radioligand binding studies indicate that tra-zodone has high and moderate affinity for humanα1- and α2-adrenoceptors, respectively (Krege et al,2000). In contrast to trazodone, m-chlorophenylpipe-razine (m-CPP) did not significantly affect caverno-sal contractions induced by electrical stimulation andexogenous noradrenaline (Saenz de Tejada et al,1991). Thus, the proerectile action of trazodone islikely to be related to the α-adrenoceptor blockingproperty of trazodone in erectile tissue.

However, m-CPP, the main metabolite of trazodone,is a serotonin agonist. m-CPP is capable of elicitingan increase in spontaneous firing of the cavernousnerve accompanied by an increase in cavernous pres-sure in the anaesthetized rat (Steers & de Groat,1989).

Subcutaneous administration of m-CPP inducespenile erection in rats. The proerectile property of m-CPP involves activation of 5-HT-2C receptors locali-zed in the lumbosacral spinal level of the rat (Millanet al, 1997; Bancila et al, 1999). The neuro-modula-tory role of m-CPP on penile erectile activity contri-buting to pharmacological action of trazodone inhuman is not clear.

Delequamine is a more specific and selective α2-adrenoceptor antagonist than yohimbine (Brown etal, 1993). α2-adrenoceptors are present on the nora-drenergic cell bodies in the locus coeruleus and theirpresynaptic terminals throughout the brain. The cen-tral effect of α2-adrenoceptor blockade by delequa-mine is an increased noradrenaline level at thesynapse by blocking re-uptake leading to sexualarousal (Bancroft, 2000). In rat mating experiments,delequamine dose dependently increased sexualbehaviour, but unlike yohimbine, it did not affect eja-culatory function, which is mediated via 5-HT-1Areceptors (Tallentire et al, 1996)

In human corpus cavernosum, norepinephrine (NE)and epinephrine may activate postsynaptic α2-adre-noceptor subtypes, in addition to activating α1-adre-noceptor subtypes, on smooth muscle cells, contribu-ting to local control of human corpus cavernosumsmooth muscle tone in vivo (Traish et al, 1997).

A centrally mediated effect of delequamine in humansis supported by the findings that intravenous infusionof low dose of the drug in the normal controls produ-ced an increase in NPT during non-REM sleep, andwith the high dose, spontaneous erections occurredjust before sleep onset (Bancroft et al, 1995).

During the waking state, normal controls reportedsignificantly higher subjective ratings of sexual arou-sal before erotic stimulation and increased likelihoodof spontaneous erections or significant prolongationof erectile response to visual erotic stimuli followinghigh dose of delequamine (Munoz et al, 1994).

As with the putative α2−adrenoceptor actionsyohimbine (see Table 1), delequamine may also havea dual MOA. Specifically, delequamine may serve asa conditioner in the CNS by blocking the prejunc-tional α2−adrenoceptors and thereby increasingnoradrenergic neurotransmission to enhance sexualfunction. In addition, delequamine may also blockdistinct prejunctional α2−adrenoceptors that aresympatholytic (blockade increases NO release; seediscussion of yohimbine above). Finally, delequami-ne may provide an additional sympatholytic compo-nent via blockade of postsynaptic α2−adrenoceptorson smooth muscle cells (again, promoting relaxa-tion; see Table 1). Obviously, clinical efficacyimplies that the balance of the potential sympatho-mimetic and sympatholytic actions favors the later.

1.IV. DELEQUAMINE

1.III. TRAZODONE

511

Nalmefene, derived from naltrexone, is a long-actingopioid receptor antagonist. Intravenous bolus admi-nistration of nalmefene in male rhesus monkeysleads to significant increases in plasma LH and tes-tosterone levels with no change in LH or prolactinpulse frequency or amplitude (Mello et al, 2000).Nalmefene treatment in older impotent men alsoincreases the activity of the hypothalamic-pituitary-gonadal axis, which manifests as a significant increa-se in serum testosterone, LH and FSH, but no chan-ge in NPT (Billington et al, 1990).

Apart from exerting inhibitory effects on male sexualdrive and performance, endogenous and exogenousopioids also exert an inhibitory influence on hypo-thalamic LH releasing hormone (LHRH), which sti-mulates the pulsatile release of LH from pituitarygonadotropes (Crowley & Simpson, 1978; Cushman,1972; McIntosh et al, 1980, Mirin et al, 1980). Nal-trexone and naloxone, which are opiate antagonists,have been shown to facilitate male copulatory beha-viour (Wu & Noble, 1986; Myers & Baum, 1979).The facilitatory effect of naloxone on masculinesexual performance in the rat is associated with adrug-induced release of LHRH (Myers & Baum,1980).

Naltrexone therapy was documented to significantlyimprove sexual performance in 11 out of 15 idiopa-thic ED patients (Fabbri et al, 1989). However, in adouble blind study of 20 patients with idiopathic ED,Brennemann et al (1993) reported no significanteffect on libido and frequency of intercourse. In bothstudies, naltrexone consistently increases the inci-dence of spontaneous early morning erectionswithout significant modification of plasma gonado-trophin levels. The efficacy of naltrexone does notappear to be correlated to the hormonal effect of nal-trexone.

Naltrexone therapy may, thus, be beneficial in EDpatients with altered central opioid tone.

Adaikan PG, Ratnam SS. Pharmacological consideration ofintracavernous drug injection in the treatment of impotence.Acta Urol Belg 1988; 56(2): 149-53.

Argiolas A, Melis MR, Murgia S, Schioth HB. ACTH- andalpha-MSH-induced grooming, stretching, yawning and peni-le erection in male rats: site of action in the brain and role ofmelanocortin receptors. Brain Res Bull 2000; 51(5): 425-31.

Bancila M, Verge D, Rampin O, Backstrom JR, Sanders-BushE, McKenna KE, Marson L, Calas A, Giuliano F. 5-Hydroxy-tryptamine2C receptors on spinal neurons controlling penileerection in the rat. Neuroscience 1999; 92(4): 1523-37.

Bancroft J, Munoz M, Beard M, Shapiro C. The effects of anew alpha-2 adrenoceptor antagonist on sleep and nocturnalpenile tumescence in normal male volunteers and men witherectile dysfunction. Psychosom Med 1995; 57(4): 345-56.

Bancroft J. Effects of alpha-2 blockade on sexual response:experimental studies with Delequamine (RS15385). Int JImpot Res 2000; 12(S1): S64-S69.

Billington CJ, Shafer RB, Morley JE. Effects of opioid bloc-kade with nalmefene in older impotent men. Life Sci 1990;47(9): 799-805.

Brennemann W, Stitz B, Van Ahlen H, Brensing KA, Kling-muller D. Treatment of idiopathic erectile dysfunction in menwith the opiate antagonist naltrexone—a double-blind study.J Androl 1993; 14(6): 407-10.

Brown CM, MacKinnon AC, Redfern WS, Hicks PE, Kilpa-trick AT, Small C, Ramcharan M, Clague RU, Clark RD,MacFarlane CB, et al. The pharmacology of RS-15385-197, apotent and selective alpha 2-adrenoceptor antagonist. Br JPharmacol 1993; 108(2): 516-25.

Crowley TJ, Simpson R. Methadone dose and human sexualbehavior. Int J Addict 1978; 13(2): 285-95.

Cushman P Jr. Sexual behavior in heroin addiction andmethadone maintenance. Correlation with plasma luteinizinghormone. N Y State J Med 1972; 72(11): 1261-5.

Dorr RT, Lines R, Levine N, Brooks C, Xiang L, Hruby VJ,Hadley ME. Evaluation of melanotan-II, a superpotent cyclicmelanotropic peptide in a pilot phase-I clinical study. Life Sci1996; 58(20): 1777-84.

Fabbri A, Jannini EA, Gnessi L, Moretti C, Ulisse S, Franze-se A, Lazzari R, Fraioli F, Frajese G, Isidori A. Endorphins inmale impotence: evidence for naltrexone stimulation of erec-tile activity in patient therapy. Psychoneuroendocrinology1989; 14(1-2): 103-11.

Krege S, Goepel M, Sperling H, Michel MC. Affinity of tra-zodone for human penile alpha1- andalpha2-adrenoceptors.BJU Int 2000; 85(7): 959-61.

McIntosh TK, Vallano ML, Barfield RJ. Effects of morphine,beta-endorphin and naloxone on catecholamine levels andsexual behavior in the male rat. Pharmacol Biochem Behav1980; 13(3): 435-41.

Mello NK, Mendelson JH, Kelly M. Acute effects of nalme-fene on LH, prolactin, and testosterone in male rhesus mon-keys. Pharmacol Biochem Behav 2000; 66(2): 275-83.

Millan MJ, Peglion JL, Lavielle G, Perrin-Monneyron S. 5-HT2C receptors mediate penile erections in rats: actions ofnovel and selective agonists and antagonists. Eur J Pharma-col 1997; 325(1): 9-12.

Mirin, SM, Meyer, RE, Mendelson, JH, Ellingboe, J: Opiateuse and sexual function. Am. J. Psychiatry. 137: 909-915,1980.

Munoz M, Bancroft J, Turner M. Evaluating the effects of an

REFERENCES

1.VI. NALTREXONE

1.V. NALMEFENE

512

alpha-2 adrenoceptor antagonist on erectile function in thehuman male. 1. The erectile response to erotic stimuli involunteers. Psychopharmacology (Berl) 1994; 115(4): 463-70.

Myers BM, Baum MJ. Facilitation by opiate antagonists ofsexual performance in the male rat. Pharmacol BiochemBehav 1979; 10(4): 615-8.

Myers BM, Baum MJ. Facilitation of copulatory performan-ce in male rats by naloxone: effects of hypophysectomy, 17alpha-estradiol, and luteinizing hormone releasing hormone.Pharmacol Biochem Behav 1980; 12(3): 365-70.

Saenz de Tejada I, Ware JC, Blanco R, Pittard JT, Nadig PW,Azadzoi KM, Krane RJ, Goldstein I. Pathophysiology of pro-longed penile erection associated with trazodone use. J Urol1991; 145(1): 60-4.

Steers WD, de Groat WC. Effects of m-chlorophenylpiperazi-ne on penile and bladder function in rats. Am J Physiol 1989;257(6 Pt 2): R1441-9.

Tallentire D, McRae G, Spedding M, Clark R, Vickery B.Modulation of sexual behaviour in the rat by a potent andselective alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197). Br J Pharmacol 1996; 118(1): 63-72.

Thody AJ, Donohoe SM, Shuster S. alpha-Melanocyte stimu-lating hormone and the release of sex attractant odors in thefemale rat. Peptides 1981; 2(2): 125-9.

Traish AM, Moreland RB, Huang YH, Goldstein I. Expres-sion of functional alpha2-adrenergic receptor subtypes inhuman corpus cavernosum and in cultured trabecular smoothmuscle cells. Recept Signal Transduct 1997; 7(1): 55-67.

Van der Kraan M, Adan RA, Entwistle ML, Gispen WH, Bur-bach JP, Tatro JB. Expression of melanocortin-5 receptor insecretory epithelia supports a functional role in exocrine andendocrine glands. Endocrinology 1998; 139(5): 2348-55.

Van der Ploeg LH, Martin WJ, Howard AD, et. al. A role forthe melanocortin 4 receptor in sexual function. Proc. Natl.Acad. Sci. 99: 11381-11386, 2002.

Vemulapalli R., Kurowski S., Salisbury B., Parker E., DavisH.: Activation of central melanocortin receptors by MT-IIincreases cavernosal presure in rabbits by the neuronal release of NO. Br. J. Pharmacol. 134; 1708-1710, 2001.

Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ,Dorr R, Levine N. Synthetic melanotropic peptide initiateserections in men with psychogenic erectile dysfunction:double-blind, placebo controlled crossover study. J Urol1998; 160(2): 389-93.

Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levi-ne N. Effect of an alpha-melanocyte stimulating hormoneanalog on penile erection and sexual desire in men with orga-nic erectile dysfunction. Urology 2000; 56(4): 641-6.

Wikberg JE, Muceniece R, Mandrika I, Prusis P, Lindblom J,Post C, Skottner A. New aspects on the melanocortins andtheir receptors. Pharmacol Res 2000; 42(5): 393-420.

Wu FM, Noble RG. Opiate antagonists and copulatory beha-vior of male hamsters. Physiol Behav 1986; 38(6): 817-25

Yohimbine is an indole alkaloid from the cortex ofthe Coryanthe yohimbe tree, which has been claimedto have aphrodisiac activity. The principal pharma-cological action of yohimbine is as an α2-adreno-ceptor antagonist. α2-adrenoceptors are located bothperipherally and centrally (especially in the locuscoeruleus neurons; see below), which are associatedwith sexual arousal and response.

Peripherally, pre- and post-junctional α2-adrenocep-tors are present in the human penile erectile tissues(Molderings et al, 1989; Traish et al, 1997). Activa-tion of presynaptic α2-adrenoceptors in erectile tis-sue inhibits the release of noradrenaline at the sym-pathetic nerve endings, hence reducing the sympa-thetic transmission (Molderings et al, 1989).

Yohimbine then, as a presynaptic α2-adrenoceptorantagonist, is expected to increase sympathetic trans-mission and promote smooth muscle contractility.However, the occurrence of distinct pre-junctionalα2-adrenoceptors in horse penile resistance arterieshas also been reported and stimulation of thesereceptors inhibit nitrergic transmitter release (Simon-sen et al, 1997). Blocking these pre-junctional α2-adrenoceptors would, therefore, effectively enhanceNO release. As such, blockade of prejunctional α2−adrenoceptors can have both sympathomimetic andsympatholytic effects at the end organ (peripheral)level; the balance of these actions presumably favorsthe latter. This might be one of the mechanisms bywhich yohimbine induces penile arterial relaxation.Recent data also indicate that yohimbine may media-te relaxation of human and rabbit corpus cavernosumvia release of nitric oxide from endothelium, whichis androgen dependent (Filippi et al, 2002). Finally,antagonism of post-junctional α2-adrenoceptors,which mediate contractions of corpus cavernosum,by yohimbine may play a role in facilitating penileerection.

Experimental data show that central α2-adrenocep-tors are implicated in the regulation of male sexualbehaviour (Sala et al, 1990). Clonidine, a selectiveα2-adrenoceptor agonist, administered intracerebro-ventricularly or in the medial preoptic area of the

2.I. YOHIMBINE

CENTRALLY AND PER-IPHERALLY ACTIVE

2.

513

hypothalamus suppressed copulatory behaviour inmale rats and yohimbine prevented the copulatorysuppression induced by clonidine (Clark, 1991).Yohimbine has also been demonstrated to increasesexual motivation in sexually experienced male ratsand induce sexual activity in sexually naïve or pre-viously inactive rats (Clark et al, 1984, 1985). Insexually exhausted intact rats, yohimbine is able toreestablish copulatory behavior whereas in ratsadministered a neurotoxin (DSP4, to cause a lesionin the central noradrenergic system), yohimbine, butnot naloxone (opioid antagonist) or 8-OH-DPAT(5HT1A agonist) restored partially sexual perfor-mance. These findings indicate that the integrity ofthe central noradrenergic system is essential forsexual behaviour (Rodriguez-Manzo & Fernandez-Guasti, 1995).

The site of action of yohimbine in human as a pro-erectile agent is not well defined. Yohimbine may actperipherally by dual mechanisms:

1) a post-junctional α2-adrenoceptor antagonist,although the predominant subtype of α-adrenocep-tors in penile tissue is of α1-subtype, and

2) By releasing relaxing factors such as nitric oxide.The effect of intracavernous yohimbine has not beendetermined, however, intracavernous injection ofanother α2-adrenoceptor antagonist, idazoxan, hadno erectogenic effect in man (Brindley, 1986).Yohimbine, as demonstrated in rats, may presumablyact through central α2-adrenoceptor increasing nora-drenergic transmission to enhance sexual function inhuman.

Phentolamine is a non-selective α-adrenoceptorantagonist with similar affinity for α1- and α2-adre-noceptors. Both post-junctional α1- and α2-adreno-ceptors mediating contractions are present in corpuscavernosum and penile vascular smooth muscle(Molderings et al, 1989; Christ et al, 1990; Traish etal., 1998; Simonsen et al, 1997). Pre-junctional α2-adrenoceptors in the corpus cavernosum modulatestimulus-evoked release of noradrenaline from sym-pathetic nerves in the erectile tissue (Molderings etal, 1989), whereas those in the horse penile resistan-ce arteries regulate the release of nitrergic transmit-ter (Simonsen et al, 1997).

Phentolamine mesylate induced relaxation of corpuscavernosum erectile tissue is thought to occur bydirect antagonism of α1- and α2-adrenoceptors, aswell as by indirect functional antagonism via a non-

adrenergic, endothelium-mediated mechanism sug-gesting nitric oxide synthase activation (Traish et al,1998; Vemulapalli & Kurowski, 2001). The clinicalutility of phentolamine is presumably a reflection ofthe contribution of adrenergic neurotransmission tothe maintained rugosity of the penis, and thus, inhi-bition of α-adrenoceptor activity alone may be suffi-cient for erection to commence (Adaikan, 1979;Adaikan et al, 1986; see Chapter 10 for a full des-cription of the role of the α-adrenoceptor pathway inpenile erection and detumescence).

Oral/intracavernosal phentolamine therefore mayfacilitate penile erection by inhibiting the functionalpredominance of α1-adrenoceptor activity that main-tains erectile tissues in a non-erect state. Attenuationof the opposing adrenergic contractile responseenhances NO-mediated corpus cavernosum relaxa-tion. Furthermore, phentolamine may delay detu-mescence, which is mediated by noradrenaline,contributing to the maintenance of penile erection.

Adaikan PG, Kottegoda SR, Karim S, Ratnam SS. Adrenergicmechanism in penile erection. Asia Pac J Pharmacol 1986; 1:141-43.

Adaikan PG. Pharmacology of human penis. MSc Thesis.University of Singapore 1979: 1-213.Brindley GS. Pilot experiments on the actions of drugs injec-ted into the human corpus cavernosum penis. Br J Pharmacol1986; 87(3): 495-500.Christ, G.J., Maayani, S., Melman, A. Pharmacological stu-dies of human erectile tissue: Characteristics of spontaneouscontractions and alterations in a-adrenoceptor responsivenesswith age and disease in isolated tissues. Br.J.Pharmacol.101:375-381, 1990.Clark JT, Smith ER, Davidson JM. Enhancement of sexualmotivation in male rats by yohimbine. Science 1984;225(4664): 847-9.Clark JT, Smith ER, Davidson JM. Evidence for the modula-tion of sexual behavior by alpha-adrenoceptors in male rats.Neuroendocrinology 1985; 41(1): 36-43.Clark JT. Suppression of copulatory behavior in male rats fol-lowing central administration of clonidine. Neuropharmaco-logy 1991; 30(4): 373-82.Filippi S, Luconi M, Granchi S, Natali A, Tozzi P, Forti G,Ledda F, Maggi M. Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation. Int J Impot Res 2002;14(4): 295-307.Molderings GJ, Gothert M, Van Ahlen H, Porst H. Noradre-naline release in human corpus cavernosum and its modula-tion via presynaptic alpha 2-adrenoceptors. Fundam ClinPharmacol 1989; 3(5): 497-504. Rodriguez-Manzo G, Fernandez-Guasti A. Participation ofthe central noradrenergic system in the reestablishment ofcopulatory behavior of sexually exhausted rats by yohimbine,

REFERENCES

2.II. PHENTOLAMINE

514

naloxone, and 8-OH-DPAT. Brain Res Bull 1995; 38(4): 399-404.Sala M, Braida D, Leone MP, Calcaterra P, Monti S, Gori E.Central effect of yohimbine on sexual behavior in the rat.Physiol Behav 1990; 47(1): 165-73.Simonsen U, Prieto D, Hernandez M, Saenz de Tejada I, Gar-cia-Sacristan A. Prejunctional alpha 2-adrenoceptors inhibitnitrergic neurotransmission in horse penile resistance arteries.J Urol 1997; 157(6): 2356-60.Traish A, Gupta S, Gallant C, Huang YH, Goldstein I. Phen-tolamine mesylate relaxes penile corpus cavernosum tissue byadrenergic and non-adrenergic mechanisms. Int J Impot Res1998; 10(4): 215-23.Traish A, Moreland RB, Huang YH, Goldstein I. Expressionof functional alpha2-adrenergic receptor subtypes in humancorpus cavernosum and in cultured trabecular smooth musclecells. Recept Signal Transduct 1997; 7(1): 55-67Vemulapalli S, Kurowski S. Phentolamine mesylate relaxesrabbit corpus cavernosum by a nonadrenergic, noncholinergicmechanism. Fundam Clin Pharmacol 2001; 15(1): 1-7.

Major research efforts have led to the production anddevelopment of compounds that are selective andpotent in inhibiting particular PDEs (Corbin andFrancis, 2002; Ballard et al, 1998; Rotella DP, 2002;Hellstrom et al, 2002; Klotz et al, 2001; Lue 2000;Montorsi et al, 2003; Padma-Nathan et al, 2001;Padma-Nathan et al, 2002; Hellstrom et al, 2003).The clinical success and public interest have resultedin the generation of an enormous amount of infor-mation and data regarding the mechanism of actionof these groundbreaking treatments for erectile dys-function. The salient aspects of this ever growingdatabase are reviewed below.

Sildenafil (Viagra™) is the first commercializedcompound in this class. This class has been recentlyjoined by vardenafil (Levitra™) and tadalafil (Cia-lis™). Vardenafil has a similar structure to sildenafilbut the structure of tadalafil is significantly different(Fig. 3). As will be discussed below, vardenafil ismore potent than sildenafil in vitro to inhibit PDE5,and this difference is explained by differences (seearrows) in molecular structures of these two com-pounds. We should note that potency is an in vitromeasure of a drug concentration that elicits anaction. It is not a direct measure of clinical efficacy.More potent does not necessarily mean more clini-cally efficient.

Part of the ring structure of sildenafil or vardenafil issimilar to that of caffeine (see dashed ovals). Thissame ring structure is similar to a ring structure incGMP. This is important since these drugs are com-petitive inhibitors of cGMP for PDE5, and they pre-sumably form some of the same molecular interac-tions as cGMP forms with amino acids in PDE5(hydrogen bonds, hydrophobic stacking interactions,van der Waals contacts, ionic interactions, etc). Eventhough the tadalafil structure differs significantlyfrom those of the other two inhibitors, its molecularmechanism of action is believed to be similar.

The normal pathway for penile erection (Fig. 4) isinitiated by sexual arousal, which stimulates releaseof nitric oxide at nerve endings in the penis. Anothersource of nitric oxide is vascular endothelial cells. Asdescribed elsewhere in this chapter, nitric oxide dif-fuses into vascular smooth muscle cells in the penilecorpus cavernosum to cause stimulation of guanylylcyclase and elevation of cGMP in these cells (Ignar-ro et al, 1990; Burnett et al, 1992). This leads to acti-vation of cGMP-dependent protein kinase (PKG),phosphorylation of several proteins, and lowering ofcell calcium, which results in smooth muscle relaxa-tion. The increased accumulation of blood in corpuscavernosum caused by this relaxation is the under-lying basis for penile erection. The pathway shownin Fig. 4 may not work properly if the cGMP level incorpus cavernosum smooth muscle cells is not eleva-ted sufficiently or if relaxation of smooth muscle inthis tissue is deficient/incomplete (Corbin and Fran-cis, 1999; Jeremy et al., 1997).

3.I. PDE 5 INHIBITORS

PERIPHERALLYACTIVE

3.

515

Figure 3 : Molecular structures of sildenafil, vardenafil,and tadalafil as compared with those for caffeine andcGMP. Arrows denote differences between structures of sil-denafil and vardenafil.

There is where the PDE5 story comes into play. Thatis, PDE5 inhibitors enhance erectile function duringsexual stimulation by penetrating into smoothmuscle cells and inhibiting PDE5, which is an enzy-me that degrades cGMP. This results in decreaseddegradation of cGMP, which maintains higher cellu-lar levels of cGMP in both corpus cavernosum andthe vessels supplying it. This increases relaxation ofthe smooth muscle, which dilates the corporeal sinu-soids resulting in increased blood flow, allowing anerection to occur. PDE5 inhibitors increase the cellcGMP by competitively inhibiting PDE5, which trig-gers penile erection. PDE5 inhibitors do not increasethe nitric oxide level, but they potentiate the nitricoxide effect to stimulate erection. Without sexualarousal, which triggers the nerve-nitric oxide path-way, these inhibitors are ineffective. The same typeof synergistic effect between PDE5 inhibitors andnitric oxide was found at the time of discovery of thecaffeine inhibitory effect on PDEs more than fortyyears ago (Robison et al., 1971), whereby caffeinewas shown to be synergistic with epinephrine to ele-vate cAMP in dog liver. In other words, caffeinealone had little if any effect on metabolism of seve-ral isolated tissues, but when added together with astimulator (such as epinephrine or glucagon) ofcAMP production, which also had minimal effectwhen added alone, caffeine had a pronounced effectto increase cAMP as well as the tissue metabolic res-ponse to cAMP. This same principle also applies tothe combination of PDE5 inhibitor and nitric oxide(sexual arousal) in the cGMP pathway that causespenile erection.

PDE5 was discovered by Corbin and colleagues(Lincoln et al, 1976; Francis et al, 1980). A cartoonof the enzyme structure is shown in Fig. 5. Each ofthe two subunits of PDE5 has a catalytic domain anda regulatory domain. The catalytic domain, but notthe regulatory domain, is the target of PDE5 inhibi-tors. The catalytic domain contains a single bindingsite for cGMP. When cGMP occupies this site thecatalytic machinery (paired black structures), whichis located very near the catalytic binding site, isbrought into close proximity and breaks the cyclicphosphate bond of cGMP to form linear 5’-GMP.This dampens or terminates cGMP action. The cata-lytic machinery has been shown to utilize divalentcations such as Zn++ (Francis et al, 1994). Becausethey have similar structures as cGMP, sildenafil orother PDE5 inhibitors can also occupy the catalyticsite, thus blocking access to cGMP. In fact, sildena-fil occupies the site about 1000 times more avidlythan does the natural substrate, cGMP. However, thePDE5 inhibitors are not broken down by the cataly-tic machinery. Occupation of the catalytic site bythese inhibitors competitively inhibits cGMP break-down since cGMP cannot bind to gain access to thecatalytic machinery. Inhibition of cGMP breakdownleads to elevation of cGMP in smooth muscle cells ofthe penile corpus cavernosum, resulting in relaxationof the muscle and penile erection.

Although the catalytic domain of PDE5 is the directtarget of PDE5 inhibitors, certain features of theregulatory domain impact the PDE5 inhibitor actionson the enzyme (Corbin et al., 2000; Corbin et al,

516

Figure 4. Regulation of penile corpus cavernosum smoothmuscle relaxation and effect of PDE5 inhibitors.

Figure 5. Cartoon of PDE5 molecular structure showingmolecular effect of PDE5 inhibitor on the catalytic domain.P = phosphate; NH2 = amino terminus.

2003). This domain contains allosteric cGMP-bin-ding sites (one or two per subunit) as well as a phos-phorylation site for negative feedback regulation ofthe enzyme. PKG phosphorylates this site about 10times faster than does PKA. When cGMP binds tothe allosteric sites, cGMP is not degraded as it is inthe catalytic site, but PDE5 enzyme functions areactivated by the binding reaction. Phosphorylationalso activates PDE5 enzyme functions. However,when PDE5 inhibitor is present, which causes cGMPelevation and phosphorylation, PDE5 inhibitor bin-ding at the catalytic site is expected to be stimulated.This means that when cGMP is elevated in smoothmuscle cells after a patient takes a PDE5 inhibitortablet, this should stimulate the catalytic site to bindmore of the inhibitor. That is, the PDE5 inhibitor sti-mulates its own efficacy. For example, were it not forthis built-in enzyme mechanism, a 200-mg doserather than 100-mg dose of a particular PDE5 inhibi-tor might be required to induce penile erection in aparticular patient.

Assuming all other factors are equal, the higher theaffinity (potency) of a PDE5 inhibitor for PDE5, thelower the expected dose of the inhibitor that will beneeded (Corbin and Francis, 2002). This concept ofpotency can be assessed by measuring the concentra-tion of a particular PDE5 inhibitor in vitro that inhi-bits PDE5 activity by 50%, and is known as theIC50. Highly potent drugs are expected to have affi-nities (IC50 values) in the nanomolar (nM) range.However, as discussed below, factors such as phar-macokinetics have strong impact on the dose requi-red. Higher potency does not mean that a PDE5 inhi-bitor has a greater clinical effect, but that less of it isneeded for the desired effect. For the PDE5 inhibi-tors, less vardenafil is required than sildenafil ortadalafil to achieve the same degree of in vitro PDE5inhibition. Vardenafil is therefore more biochemical-ly potent than are sildenafil and tadalafil, althoughnot necessarily more efficacious. Based on in vitropotencies, it would be predicted that a lower dosageof vardenafil than sildenafil would be required tocause penile erection in men. This appears to be thecase since 5-20 mg doses of vardenafil are recom-mended compared with 25-100 mg doses of sildena-fil. The recommended doses of tadalafil are alsolower than those of sildenafil, but since these twodrugs have similar biochemical potencies, the expla-nation for lower dosage is not clear at this time.

There are methods in addition to classical IC50 tomeasure potency of a drug. The Corbin group hasrecently measured the strength of binding of radiola-

beled PDE5 inhibitors to PDE5, and the value obtai-ned by this method is termed KD instead of IC50(Corbin et al, 2003). As compared with IC50, mea-surement of KD is a more direct method of determi-ning potency. The KD of a PDE5 inhibitor obtainedusing this approach should approach the IC50 of thesame PDE5 inhibitor. In fact, our results show thatthe KD for sildenafil, vardenafil, or tadalafil approxi-mates the IC50 for each compound. The finding thatthe value of KD approaches the value of IC50 foreach inhibitor suggests that these compounds do notbind to an appreciable extent to sites on PDE5 otherthan the catalytic domain. The approach of determi-ning KD not only provides a new tool to measurePDE inhibitor potency but may also reveal new pro-perties of PDE5 and PDE5 inhibitors which were notpossible to study previously. These include the PDE5on-rates and off-rates of PDE5 inhibitors, whichshould help to predict time of onset and duration ofinhibitor action in patients. The radiolabeled inhibi-tors could also be used to search for the presence ofnon-PDE PDE5 inhibitor-binding proteins in bodytissues, which might suggest the potential for sideeffects of a particular PDE5 inhibitor.

Based on comparative IC50 values, the potency ofsildenafil is about 1 million times higher than that ofcaffeine (Corbin and Francis, 1999). Other experi-mental PDE inhibitors have intermediate potencies.According to literature values, the in vitro biochemi-cal potencies of the three new commercial PDE5inhibitors are within the same range of each other,albeit vardenafil is more potent than the other twoinhibitors (Corbin and Francis, 2002). The in vitropotency of a PDE5 inhibitor is not the same as effi-cacy. As discussed below, efficacy is based on theactual in vivo (clinical), effects of the inhibitor.

The biochemical selectivity of an inhibitor for PDE5is a key factor in determining its side-effect profile(Corbin and Francis, 2002). Once a large enoughseparation exists between the affinity (IC50) of theinhibitor for PDE5 and its affinity for non-targetPDEs (or other proteins), the less likely it is that itcan achieve sufficient plasma concentrations to acti-vate the non-target site at therapeutic doses. ForPDE5 inhibitors, selectivity is usually expressed interms of potency (IC50) to inhibit PDE5 as opposedto inhibiting any others in the PDE family. The selec-tivity is computed by dividing the IC50s of the twocompounds that are compared. The PDEs are com-prised of 11 families of enzymes that catalyze the ter-mination of second messenger activity in cells bybreaking the phosphodiester bond of either cAMP or

517

cGMP. Eleven distinct families have been identified(PDE1 to PDE11) that are known or implicated in abroad range of cellular functions. Within some fami-lies, more than a single gene exists, for a total of atleast 25 PDE genes, and some of these genes havemultiple products brought about by alternativemRNA splicing, resulting in a grand total of morethan 50 PDE forms (Francis et al., 2001). PDE5,which is cGMP-specific, exhibits only one gene,although its mRNA can be spliced to yield at leastthree isoforms. However, it should be noted thatthese isoforms may not differ significantly in theircatalytic domains, which is the site of action ofPDE5 inhibitors. PDE5 is present in high concentra-tions in the smooth muscle of corpora cavernosa ofthe penis (Gopal et al, 2001). Sildenafil and vardena-fil cross-react slightly with PDE6, i.e., their IC50sfor PDE5 are only 4-10 fold lower than those forPDE6. PDE6 is expressed in the retina. This mayexplain the complaint of some patients that sildenafilcauses visual disturbances. Tadalafil cross reactswith PDE11 to some extent, but the consequences ofthis effect are unknown. PDE11 is expressed in testi-cular cells, cardiac muscle, smooth muscle and thepituitary. Neither of the three PDE11 inhibitorscross-reacts to a large extent with any of the otherPDEs except for PDE6 and PDE11, i.e., the IC50s ofthese compounds for PDE5 are more than 1000 timeslower than those for most of the other PDEs. Exceptfor visual disturbances, the other reported sideeffects of PDE5 inhibitors (headaches, flushing,slight lowering of blood pressure, etc) are likely cau-sed by PDE5 inhibition in smooth muscle tissuesoutside the penile corpus cavernosum.

In addition to biochemical properties discussed above,pharmacokinetic properties of PDE5 inhibitors (inges-tion, movement in the circulation, tissue uptake, eli-mination) have great impact on efficacy (Corbin andFrancis, 2002). There are several common pharmaco-kinetic parameters that can be measured and quanti-fied that describe bodily distribution of a PDE5 inhi-bitor (Table 2). The bioavailability, maximum plasmaconcentration (Cmax), the time (Tmax) required forattaining Cmax, and time (t1/2) required for elimina-tion of one-half of the inhibitor from plasma are allimportant factors. The bioavailability, which is thepercentage of ingested inhibitor that actually appearsin the plasma, is about one-third as much for vardena-fil (15%) as that for sildenafil (40%). The bioavaila-bility for tadalafil is unknown at present.

Sildenafil, vardenafil, and tadalafil have broadlysimilar Tmax (sildenafil and vardenafil Tmax occurs

in less than 1 hour, the tadalafil Tmax occurs in 2hours), but the Cmax of vardenafil is significantlylower than that for either of the other two inhibitors.This might be expected based on the higher bioche-mical potency of vardenafil. The t1/2 of tadalafil isconsiderably longer than that of the other two PDE5inhibitors, which could be due to slower intestinalabsorption and/or slower degradation of this drug bythe liver, or it could be due to other factors. Theextended t1/2 of tadalafil provide a much longer the-rapeutic effect (Porst et al 2003), which may be pre-ferred for spontaneous sexual activity, but couldexpose the patient to greater risk of side effects.

PDE5 inhibitors are believed to be degraded in theliver. Therefore, since they are not degraded byPDE5 or any other enzyme in smooth muscle cells ofcorpus cavernosum, they must dissociate fromPDE5, exit the smooth muscle cells and then betransported to the liver via the bloodstream beforethey can be degraded. The rate of exit of a PDE5inhibitor from smooth muscle cells should be consi-dered when comparing PDE5 inhibitors since thiscould affect its duration of action. Disappearance ofthe inhibitor from plasma may imply, but does notprove, its disappearance, or clearance, from the cellsin which it produces its effects. Since the inhibitorbinds tightly to PDE5 in these cells, this could signi-ficantly retard its exit from these cells and prolongeffects of PDE5 inhibitors in patients. It is concei-vable that PDE5 inhibitors with higher affinities forPDE5 would dissociate from the enzyme more slow-ly, resulting in a more retarded clearance from corpuscavernosum cells. Studies of clearance of PDE5 inhi-bitors from plasma are documented, but studies ofclearance of these inhibitors from smooth musclecells are rare.

518

Patterson B et al. 4th Congress of ESSIR; 2001; Rome, Italy.2. Viagra USPI [package insert]. 2000. 3. Sasche et al. AUA. 2001.

Table 2 : Pharmacokinetic Parameters of the SelectivePDE5 Inhibitors

Ballard SA, Gingell CJ, Tang K, et al.: Effects of sildenafil onthe relaxation of human corpus cavernosum tissue in vitro andon the activities of cyclic nucleotide phosphodiesterase iso-zymes. J Urol 1998, 159:2164-2171.

Burnett AL, Lowenstein CJ, Bradt DS, Chang TSK, and Sny-der SH, (1992) Nitric oxide in the penis: physiology andpathology. Science 257, 401-403.

Corbin JD, Blount MA, Weeks JL, 2nd, Beasley A, Kuhn KP,Ho YS, Saidi LF, Hurley JH, Kotera J and Francis SH (2003)[3H] Sildenafil binding to phosphodiesterase-5 is specific,kinetically heterogeneous, and stimulated by cGMP. MolPharmacol 63:1364-72.

Corbin JD and Francis SH (1999) Cyclic GMP phosphodies-terase 5: target for sildenafil. J. Biol. Chem. 274:13729-13732.

Corbin JD and Francis SH (2002) Pharmacology of phospho-diesterase-5 inhibitors. Int. J. Clin. Pract. 56:453-9.

Corbin JD, Turko IV, Beasley A and Francis SH (2000) Phos-phorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allostericcGMP-binding activities. Eur J Biochem 267:2760-2767.

Francis SH, Colbran JL, McAllister-Lucas LM, and CorbinJD (1994) Zinc interactions and conserved motifs of thecGMP-binding cGMP-specific phosphodiesterase suggestthat it is a zinc hydrolase. J Biol Chem 269:22477-22480.

Francis SH, Lincoln TM and Corbin JD (1980) Characteriza-tion of a novel cGMP binding protein from rat lung. J. Biol.Chem. 255, 620-626.

Francis SH, Turko IV and Corbin JD (2001) Cyclic nucleoti-de phosphodiesterases: relating structure and function. Prog.Nucleic Acid Res. Mol. Biol. 65:1-52.

Gopal VK, Francis SH and Corbin JD (2001) Allosteric sitesof phosphodiesterase-5 (PDE5). A potential role in negativefeedback regulation of cGMP signaling in corpus caverno-sum. Eur. J. Biochem. 268:3304-3312.

Hellstrom WJ, Gittelman M, Karlin G, et al.: Vardenafil fortreatment of men with erectile dysfunction: efficacy and safe-ty in a randomized, double-blind, placebo-controlled trial. JAndrol 2002, 23:763-771.

Hellstrom WJ, Gittelman M, Karlin G, et al.: Sustained effi-cacy and tolerability of vardenafil, a highly potent selectivephosphodiesterase type 5 inhibitor, in men with erectile dys-function: results of a randomized, double-blind, 26-week pla-cebo-controlled pivotal trial. Urology 2003, 61:8-14.

Ignarro LJ, Bush PA, Buga GM, et al.: Nitric oxide and cyclicGMP formation upon electrical field stimulation cause relaxa-tion of corpus cavernosum smooth muscle. Biochem BiophysRes Commun 1990, 170:843-850.

Jeremy JY, Ballard SA, Naylor AM, Miller MA and AngeliniGD (1997) Effects of sildenafil, a type-5 cGMP phosphodies-terase inhibitor, and papaverine on cyclic GMP and cyclicAMP levels in the rabbit corpus cavernosum in vitro. Br JUrol 79:958-963.

Klotz T, Sachse R, Heidrich A, et al.: Vardenafil increasespenile rigidity and tumescence in erectile dysfunction

patients: a RigiScan and pharmacokinetic study. World J Urol2001, 19:32-39.

Lincoln TM, Hall CL, Park CR and Corbin JD (1976) Gua-nosine 3’:5’-cyclic monophosphate binding proteins in rat tis-sues. Proc. Natl. Acad. Sci. USA. 73:2559-2563

Lue TF: Erectile Dysfunction. N Engl J Med 2000, 324:1801-1813.

Montorsi F, Salonia A, Deho F, et al: Pharmacological mana-gement of erectile dysfunction. BJU Int 2003, 91:446-454.

Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L,Rosen R Efficacy of tadalafil for the treatment of erectile dys-function at 24 and 36 hours after dosing: a randomizedcontrolled trial. Urology. 2003 Jul;62(1):121-5

Robison GA, Butcher RW and Sutherland EW (1971) CyclicAMP. Academic Press, New York.

Rotella DP: Phosphodiesterase 5 inhibitors: current statusand potential applications. Nat Rev Drug Discov 2002, 1:674-682.

Vasoactive intestinal peptide (VIP) is a naturallyoccurring neurotransmitter. VIPergic nerves are mostdensely concentrated in the penis around the puden-dal arteries and in the erectile tissue of the corpuscavernosum. VIP is known to exert regulatoryactions on blood-flow, secretion, and muscle tone. Itspresence in considerable amounts in the male genitaltract suggests that this peptide neurotransmitter maybe important in the nervous control of male externalgenitalia (Polak et al, 1981).

VIP co-localizes with NOS within the perivascularand trabecular nerve fibres innervating the penis(Ehmke et al, 1995). Most of these NO- and VIP-containing nerves appear to be cholinergic, sincethey also contain vesicular acetylcholine transporter,a specific marker for cholinergic neurons (Hedlundet al, 2000). Other VIP-related peptides such asPHM, PACAP and helospectin (Hel-1) are also co-localized with VIP in nerve structures within thehuman cavernous tissue (Kirkeby et al, 1992, Hed-lund et al, 1995). These peptides concentration-dependently relaxed corpus cavernosum and circum-flex vein preparations in vitro. Their putative roles asneurotransmitters and/or neuromodulators in the ner-vous control of penile erection are yet to be clearlyestablished.

Though VIP is a potent relaxant of both the corpuscavernosum and penile vascular smooth muscle invitro, the ineffectiveness of VIP-antiserum to inhibitthe neurogenic relaxation in corpus cavernosumstrips suggests that VIP may not be released from the

3.II. VASOACTIVE INTESTINALPOLYPEPTIDE

REFERENCES

519

nerves during field stimulation (Adaikan et al,1986a). Furthermore, the inability of VIP to inducepenile rigidity adequate for intromission when injec-ted intracavernously in potent (Adaikan et al, 1986a)and impotent men (Roy et al, 1990) indicates that itis not likely to be the primary neurotransmittermediating penile erection.

The effects of VIP are mediated by a specific mem-brane-bound receptor linked to adenylate cyclase viaa stimulatory G-protein. VIP has been shown to ele-vate cAMP concentrations in cavernosal tissueswithout affecting cGMP levels (Miller et al, 1995;Hedlund et al, 1995).

Nitric oxide, the NANC neurotransmitter of primaryimportance in regulating corpus cavernosum smoothmuscle relaxation, is derived from L-arginine bynitric oxide synthase (NOS). As L-arginine is also asubstrate of arginase, NO production is likely to belinked to the regulation of both NOS and arginase.The decreased NOS nerves and upregulated arginaseII expression/activity found in diabetic corpus caver-nosum, which is accompanied by a decrease in erec-tile function, suggests that decreased NO synthesismay play a role in diabetic erectile dysfunction(Bivalacqua et al, 2001). Alterations in the penile L-arginine-NO pathway observed in atheroscleroticand hypercholesterolaemic penile vascular bed mayalso result in reduction in NO bioavailability leadingto ED. Recent studies show that L-arginine augmentsendothelium-dependent vasodilation in hypercholes-terolaemic rabbits and human (Girerd XJ et al, 1990;Creager et al, 1992). The rationale for L-arginine the-rapy is therefore related to the supposition that dieta-ry supplementation with NO-precursor L-argininemay normalize endothelium-dependent vasodilationand as such could have a beneficial effect in the treat-ment of erectile dysfunction. Based on this rationale,as with other combination therapies, it is conceivablethat oral co-administration of L-arginine with yohim-bine may be effective in improving erectile functionin mild to moderate erectile dysfunction because ofthe complementary actions of the α2-adrenoceptorantagonist and the NO releasing effects of yohimbi-ne. (see Lebret et al, 2002; see yohimbine discussionabove).

PGE1 produced relaxation of human corpus caver-nosum smooth muscle and this relaxant activity wasfirst described by Karim and Adaikan (1975) andAdaikan et al in 1983. This was followed by themechanism of action and use of PGE1 for the treat-ment of erectile dysfunction (Adaikan et al, 1986b;Ishii et al, 1986; Virag & Adaikan, 1987). Of note,the first competitive Ginestie Prize by the ISIR wasawarded to PG Adaikan for identifying conventionalreceptors and the use of PGE1 for the treatment oferectile dysfunction in 1986, 2nd World Meeting ofImpotence, Prague.

PGE1 mediates relaxation of corpus cavernosumsmooth muscle via activation of EP prostaglandinreceptors (EP2/4) by increasing the intracellularconcentration of cAMP in corpus cavernosum smoo-th muscle (Palmer et al., 1994; Lin et al, 1995; Trai-sh et al., 1997; Moreland et al., 2001). PGE1-indu-ced relaxation of human corpus cavernosum is asso-ciated with activation of KCa channels, leading tohyperpolarisation and alterations in transmembraneCa2+ flux (Lee et al, 1999). PGE1 may also act byinhibiting the release of noradrenaline from sympa-thetic nerves (Molderings et al, 1992) and suppres-sing angiotensin II secretion in the cavernosal tissues(Kifor et al, 1997).

PGE1 is metabolised by the 15-hydroxydehydroge-nase present in the corpus cavernosum (Roy et al,1989). The ability of human corpus cavernosum todegrade PGE1 probably aids in regulating the activi-ty of PGE1 and reducing the risk of undesirable sideeffects such as prolonged erection and priapism.

PGE1 suppressed the induction of collagen synthesisby TGF-β1 in cultured human corpus cavernosumsuggesting that PGE1 and TGF-β1 may play a keyrole in modulation of collagen synthesis and in theregulation of fibrosis of the corpus cavernosum(Moreland et al, 1995). This suppressant effectseems to correlate with the low incidence of localfibrotic lesions reported in PGE1 treated ED patients(Porst, 1996) and the unaltered intracavernous struc-tures in the 5 patients with biopsies performed onlyafter intracavernous PGE1 injection (Wespes et al,2000).

3.IV. ALPROSTADIL (PGE1)

3.III. L-ARGININE

520

Intracavernosal papaverine injection was the first cli-nically effective pharmacological therapy for ED.Papaverine is a nonopiate derivative of poppy plant(Papaver somniferum). Papaverine is a smoothmuscle relaxant. In vitro, papaverine evoked relaxa-tion of isolated corpus cavernosum smooth strips,penile arteries, cavernous sinusoids and the penileveins and attenuated contractions induced by stimu-lation of adrenergic nerves and exogenous noradre-naline (Adaikan & Ratnam 1988; Kirkeby et al,1990). In addition, in vivo studies in the rat modeldocumented that intracavernous injection of papave-rine elicited a significant and prolonged increase inintracavernous pressure (Rehman et al., 1997).Consistent with these observations, injection with 80mg papaverine in normal volunteers and subjectswith psychogenic impotence produced rigid erec-tions. Papaverine caused marked vasodilation of thepenile arteries and decreased venous outflow asrecorded by Doppler (Virag et al, 1984).

Papaverine is a nonspecific phosphodiesterase inhi-bitor that initiates an increase in intracellular cAMPand cGMP leading to corporal smooth musclerelaxation and penile erection. Papaverine may alsoregulate cavernosal smooth muscle tone via inhibi-tion of voltage-dependent L-type Ca2+ channelsindependent of cAMP as demonstrated in trachealsmooth muscle and suppression of angiotensin IIsecretion in cavernosal tissue (Iguchi et al, 1992;Kifor et al, 1997).

Phentolamine, papaverine, PGE1, VIP and linsido-mine are the vasoactive agents most commonly usedin combination therapy to treat erectile dysfunction.Combination therapy is not only predictably moreefficacous as a result of well-planned strategiesbased on sound pharmacological principles, it is alsoassociated with a reduction in incidence of sideeffects and cost per dose.

In vitro studies on human and rabbit cavernosalstrips demonstrated that phentolamine significantlypotentiated relaxation induced by sildenafil, VIP andPGE1. These vasodilators also significantly enhan-ced relaxation induced by phentolamine in the caver-nosal tissue strips. The enhancement by phentolami-

ne of VIP and PGE1-induced relaxation (cAMP-mediated) suggests a synergistic interaction whilethe interaction between phentolamine and sildenafil(cGMP-mediated) appears to be additive (Kim et al,2000). The same investigators also show that silde-nafil and PGE1 has additive and synergistic effectrespectively with phentolamine-induced relaxation.

Hence, in combination therapy employing phentola-mine as an adjunct, reducing the predominance ofadrenergic tone through the blockade of α-adreno-ceptors, increases the efficacy of vasodilators thatinitiate erection via other independent relaxatorypathways.

Adaikan PG, Kottegoda SR, Ratnam SS. Is vasoactive intes-tinal polypeptide the principal transmitter involved in humanpenile erection? J Urol 1986a; 135(3): 638-40.

Adaikan PG, Ratnam SS. Pharmacological consideration ofintracavernous drug injection in the treatment of impotence.Acta Urol Belg 1988; 56(2): 149-53.

Adaikan PG, Karim SM, Kottegoda SR, Ratnam SS. Choli-noreceptors in the corpus cavernosum muscle of the humanpenis. J Auton Pharmacol 1983; 3(2): 107-11.

Adaikan PG, Kottegoda SR, Karim S, Ratnam SS. Adrenergicmechanism in penile erection. Asia Pac J Pharmacol 1986b;1: 141-43.

Adaikan PG, Kottegoda SR, Ratnam SS. A possible role forprostaglandin E1 in human penile erection. In: Abstracts of

the 2nd World Meeting on Impotence, Prague, 1986: 2: 6.Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, Champion HC.Increased expression of arginase II in human diabetic corpuscavernosum: in diabetic-associated erectile dysfunction. Bio-chem Biophys Res Commun 2001; 283(4): 923-7.Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, DzauVJ, Cooke JP. L-arginine improves endothelium-dependentvasodilation in hypercholesterolemic humans. J Clin Invest1992; 90(4): 1248-53.Ehmke H, Junemann KP, Mayer B, Kummer W. Nitric oxidesynthase and vasoactive intestinal polypeptide colocalizationin neurons innervating the human penile circulation. Int JImpot Res 1995; 7(3): 147-56.Girerd XJ, Hirsch AT, Cooke JP, Dzau VJ, Creager MA. L-arginine augments endothelium-dependent vasodilation incholesterol-fed rabbits. Circ Res. 1990; 67(6): 1301-08.Hedlund P, Alm P, Ekstrom P, Fahrenkrug J, Hannibal J, Hed-lund H, Larsson B, Andersson KE. Pituitary adenylate cycla-se-activating polypeptide, helospectin, and vasoactive intesti-nal polypeptide in human corpus cavernosum. Br J Pharma-col 1995; 116(4): 2258-66.Hedlund P, Ny L, Alm P, Andersson KE. Cholinergic nervesin human corpus cavernosum and spongiosum contain nitricoxide synthase and heme oxygenase. J Urol 2000; 164(3 Pt1): 868-75.

REFERENCES

3.VI. COMBINATIONS

3.V. PAPAVERINE

521

Iguchi M, Nakajima T, Hisada T, Sugimoto T, Kurachi Y. Onthe mechanism of papaverine inhibition of the voltage-depen-dent Ca++ current in isolated smooth muscle cells from theguinea pig trachea. J Pharmacol Exp Ther 1992 ; 263(1): 194-200.

Ishii N, Watanabe H, Irisawa H, Kikuchi Y, Kawamura S,Suzuki K, Chiba, R, Tokiwa, M, Shirai M. Studies on malesexual impotence. Report 18. Therapeutic trial with prosta-glandin E1 for organic impotence. Nippon Hinyokika GakkiZasshi. 77: 954-962, 1986.

Karim SMM, Adaikan PG. In: Physiological roles and phar-macological actions of prostaglandins in relation to humanreproduction. In Prostaglandins and Reproduction. Ed: SMMKarim, MTP Press Ltd, Lancaster, 1975, p23-75.

Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P,Dluhy RG. Tissue angiotensin II as a modulator of erectilefunction. I. Angiotensin peptide content, secretion and effectsin the corpus cavernosum. J Urol 1997; 157(5): 1920-5.

Kim NN, Goldstein I, Moreland RB, Traish AM. Alpha-adre-nergic receptor blockade by phentolamine increases the effi-cacy of vasodilators in penile corpus cavernosum. Int J ImpotRes 2000; 12 Suppl 1: S26-36.

Kirkeby HJ, Fahrenkrug J, Holmquist F, Ottesen B. Vasoacti-ve intestinal polypeptide (VIP) and peptide histidine methio-nine (PHM) in human penile corpus cavernosum tissue andcircumflex veins: localization and in vitro effects. Eur J ClinInvest 1992; 22(1): 24-30.Kirkeby HJ, Forman A, Andersson KE. Comparison of thepapaverine effects on isolated human penile circumflex veinsand corpus cavernosum. Int J Impot Res 1990; 2: 49-54.Lebret T, Herve JM, Gorny P, Worcel M, Botto H. Efficacyand safety of a novel combination of L-arginine glutamateand yohimbine hydrochloride: a new oral therapy for erectiledysfunction. Eur Urol 2002; 41(6): 608-13.Lee SW, Wang HZ, Zhao W, Ney P, Brink PR, Christ GJ.Prostaglandin E1 activates the large-conductance KCa chan-

nel in human corporal smooth muscle cells. Int J Impot Res1999; 11(4): 189-99.Lin JS, Lin YM, Jou YC, Cheng JT. Role of cyclic adenosinemonophosphate in prostaglandin E1-induced penile erectionin rabbits. Eur Urol 1995; 28(3): 259-65.Miller MA, Morgan RJ, Thompson CS, Mikhailidis DP, Jere-my JY. Effects of papaverine and vasointestinal polypeptideon penile and vascular cAMP and cGMP in control and dia-betic animals: an in vitro study. Int J Impot Res 1995; 7(2):91-100.Molderings GJ, van Ahlen H, Gothert M. Modulation of nora-drenaline release in human corpus cavernosum by presynap-tic prostaglandin receptors. Int J Impot Res 1992; 4: 19-25.Moreland RB, Traish A, McMillin MA, Smith B, Goldstein I,Saenz de Tejada I. PGE1 suppresses the induction of collagensynthesis by transforming growth factor-beta 1 in human cor-pus cavernosum smooth muscle. J Urol 1995; 153(3Pt1):826-34.Moreland, R.B., Albadawi, H., Bratton, C., Patton, G., Gold-stein, I., Traish, A. and Watkins, M.T.: O2-dependent prosta-

noid synthesis activates functional PGE receptors on corpuscavernosum smooth muscle. Am. J. Physiol. 281: H552-H558, 2001.

Palmer, L., Valcic, M., Melman, A., Giraldi, A., Wagner, G.,Melman, A. & Christ, G.J.: Characterization of cAMP accu-mulation in cultured human corpus cavernosum smoothmuscle cells. J. Urol. 152:1308-1314, 1994.Polak JM, Gu J, Mina S, Bloom SR. Vipergic nerves in thepenis. Lancet 1981; 2(8240): 217-9.Porst H. The rationale for prostaglandin E1 in erectile failure:a survey of worldwide experience. J Urol 1996; 155(3): 802-15.Rehman, J., Chenven, E., Brink, P.R., Grine, B., Walcott, B.,Melman, A., & Christ, G.J.: Diminished neurogenic-, but notpharmacologic-induced intracavernous pressure responses inthe 3 month Streptozotocin (STZ)-diabetic rat. Am. J. Phy-siol., 272: H1960-H1971, 1997.Roy AC, Adaikan PG, Sen DK, Ratnam SS. Prostaglandin 15-hydroxydehydrogenase activity in human penile corporacavernosa and its significance in prostaglandin-mediatedpenile erection. Br J Urol 1989; 64(2): 180-2.Roy JB, Petrone RL, Said SI. A clinical trial of intracavernousvasoactive intestinal peptide to induce penile erection. J Urol1990; 143(2): 302-4.Traish, A.M., Moreland, R.B., Gallant, C., Huang, Y.H. &Goldstein, I.: G-protein-coupled receptor agonists augmentadenylyl cyclase activity induced by forskolin in human cor-pus cavernosum smooth muscle cells. Recept. Signal Trans-duct. 7: 121-132, 1997.Virag R, Frydman D, Legman M, Virag H. Intracavernousinjection of papaverine as a diagnostic and therapeuticmethod in erectile failure. Angiology 1984; 35(2): 79-87.Virag R, Adaikan PG. Effects of prostaglandin E1 on penileerection and erectile failure. J Urol 1987; 139: 1010.Wespes E, Sattar AA, Noel JC, Schulman CC. Does prosta-glandin E1 therapy modify the intracavernous musculature? JUrol 2000; 163(2): 464-6.

Topical therapy for the treatment of ED has beenproposed as one means to circumvent some of thenegative factors associated with ICI (intracavernousinjection) and IUS (intrurethral suppositories). Thesetherapies have an intrinsic appeal to many patients.Currently, topical therapies for the treatment of erec-tile dysfunction remain in clinical trials and have yetto be released for widespread use. However, topicalapplications have the potential to avoid the systemiceffects noted with oral therapies while being percei-ved as minimally invasive in so far as it does notrequire needles or intraurethral instrumentation.Topical therapy may also provide benefit to patientsunresponsive to systemic therapy or who use medi-cations which cannot be taken along with such oraltreatments (nitrate use). That is, the overall goal isthe local treatment of a local problem.

TOPICAL THERAPIES 4.

522

A short introduction to the major concepts and com-plications of using topical agents for the treatment oferectile dysfunction seems prudent. The transdermalroute is a well established technology that providesdurable and constant plasma levels of drugs such ashormonal replacements, narcotics and vasodilators.When it comes to local penile therapy using directsmooth muscle relaxants, previous experienceconcerning the duration and onset of actionemployed for these other indications may not provi-de useful attributes. Several issues, in particular, areworth mentioning:

1) High systemic concentrations are undesirable asthey may result in an unacceptable level of adverseevents.

2) Agents may be largely metabolized in the firstpass through the lungs or liver.

3) The vasoactive agent(s) needs to reach the corpo-ra cavernosa in a timely fashion with the effective(highest) concentration.

Topical penile therapy, therefore, entails a unique setof anatomic and physiologic considerations. Thereare several anatomic/fascial layers between the peni-le skin and the corpus cavernosa. The tunica albugi-nea is presumed to be difficult to penetrate due toits thick layers of collagen. Therefore, topical treat-ment trials have emphasized exposure to the glanspenis as it has direct venous communication to thecorpora cavernosa (Becher et al., 1998; McVary etal., 1999). The skin itself is a relatively impermeabletissue due to the stratum corneum. The horny cells atthe stratum corneum are bonded with a very tightintercellular lipid matrix bilayer that makes the pas-sage of drugs challenging (Gurny et al., 1993). Toovercome this barrier investigators have used pene-tration enhancers which permeate this layer andreach the subdermis. Fortunately, the penis and scro-tum are unique in that their stratum corneum is themost permeable of all anatomic locations tested.Depending on the molecular structure of the agenttested there can be nearly 100% absorption of topicalagents applied to these areas. Again, exposure to theglans affords a more easily «breached» layer. Otherskin regions (e.g.. back and palms) are particularlyimpermeable (Maibach et al., 1971). An additionalfactor confounding efficient delivery of drug is therich vasculature of the deep dermis which may«steal» the drugs to the systemic circulation.

With such an assortment of confounding factors onewonders exactly how gel applied to the penis couldever induce an erection. One attractive possibility isthat gel applied to the glans is rapidly absorbedthrough the porous skin of the glans into the venousvasculature of the corpora spongiosum. From thatlocation it could travel into the corpora cavernosaakin to the intraurethral delivery of drug (Wolfson etal., 1993; Padma-Nathan et al., 1997). The knownabsorptive nature of the penile skin and glans makethis a real possibility (Maibach et al., 1971). If this isthe case then delivery of drug to the shaft of the peniswould seem superfluous and possibly only contribu-te to penile skin discomfort. Alternatively, the drugapplied to the skin of the penis could theoretically beabsorbed through the skin, the tunica of the corporalbodies and thus into the cavernous tissues. The largedistance, multiple tissues layers and unknown per-meability of the tunica makes this a formidable drugdelivery challenge. A third more remote possibilityinvolves the systemic absorption, recirculation anddelivery of drug to the penile tissues. Systemic levelshave been measured with the penile skin applicationof papaverine and minoxidil proving that absorptiondoes occur. However, its presence in the systemiccirculation does not prove its role in the erectile res-ponse (Kim et al., 1995; Clark et al., 1994). All of theabove mentioned possibilities are expected to beinefficient at transfer of active agents thus requiringa large amount of drug to compensate the losses inthe pathway.

Most of the delivery systems currently in use fortopical therapy are intended for slow and steadyrelease of the medications such as those used in hor-monal, analgesic or narcotic patches. This slowerprocess is not effective as an erection initiator as thedrug flux is likely to be low. Investigators are cur-rently trying permeation enhancers to increase drugflux speed. In order to achieve a rapid and efficientpenetration the formulation needs to have sufficientpenetration enhancer to help transfer (flux) the acti-ve agent with good tolerance (no significant irrita-tion), and release the drug at the site of action (rightbondage).

Several transdermal enhancers incorporated as oneof the excipients in topical formulations have beenreported (Becher et al., 1998; McVary et al., 1999;Kim et al., 1995; Samour et al., 1989; Pelham et al.,1995). The task of these enhancers is to: 1) Disruptthe stratum corneum lipid bilayer, 2) Interact withthe membrane keratin, 3) Produce a weak interactionwith the drug molecule, and 4) Reverse all actions in

GENERAL PRINCIPLES OFTOPICAL AGENTS

523

a short time. The available evidence indicates thatsuch agents enhance skin penetration by altering thefluidity of lipids in the stratum corneum, without anyinteraction with the chemical whose skin permeabili-ty is enhanced.

Organic nitrate donors were the first topical agents tobe used in the treatment of erectile dysfunction(Mudd, 1977). Case reports have demonstrated thatblood flow to the penis and tumescence are increasedafter application of a nitro based paste (Owen et al.,1989; Nunez & Anderson, 1993). The local effectson penile blood flow appear to be crucial since appli-cation of such gels elsewhere on the body do notinduce erections. Topical minoxidil has also beenreported in placebo controlled double masked trials(Clark et al., 1994; Cavallini, 1991). In one study,Cavallini reported 2% minoxidil as superior to 10%nitroglycerin cream in inducing improved penilehemodynamics and with fewer side effects.

Alprostadil is a natural occurring prostaglandin E1.Alprostadil and other prostaglandins in the E seriesare naturally present in the seminal vesicles, thecavernous tissues of males and in the placenta andductus arteriosus of the fetus. Various formulationsand injection techniques, urethral suppositories andgels using PGE-1 have been used in the treatment oferectile dysfunction over the past 15 years.

Alprostadil relaxes smooth muscle of the corpuscavernosum. As described elsewhere in this section,several mechanisms of action have been proposed.Undeniably, its effects are due to increasing the intra-cellular concentrations of cAMP, via a stereospecificactivation of the membrane bound receptors. In par-ticular, PGE1 mediates relaxation of corpus caverno-sum smooth muscle via activation of the EP prosta-glandin receptor (EP2/4) to increase the intracellularconcentration of cAMP in corpus cavernosum smoo-th muscle (Palmer et al., 1994; Lin et al, 1995; Cahnet al., 1996; Traish et al., 1997; Moreland et al.,2001). PGE1-induced relaxation of human corpuscavernosum is associated with activation of KCachannels, leading to hyperpolarisation and altera-tions in transmembrane Ca2+ flux (Lee et al, 1999).

Many of these actions are presumably mediated byprotein kinase A. PGE1 may also act by inhibitingthe release of noradrenaline from sympathetic nerves(Molderings et al, 1992) and suppressing angiotensinII secretion in the cavernosal tissues (Kifor et al,1997).

The physiologic endpoint is dilation of the caverno-sal arteries, relaxation of the corporal smoothmuscle, and therefore, is accompanied by increasedarterial inflow velocity and increased venous flowresistance. As a result, the lacunar spaces expand andblood becomes entrapped secondary to compressionof venules against the tunica albuginea. To achieveadequate tumescence and rigidity the tunica albugi-nea must be sufficiently stiff to compress the pene-trating venules and thus block venous outflow. Thisprocess is also referred to as the corporal veno-occlusive mechanism. Alprostadil does not directlyeffect ejaculation or orgasm.

Topical minoxidil has been recently used as an inves-tigational drug in the treatment of erectile dysfunc-tion. Although little can be said about its role in thatregard, there is an extensive literature on its use as anantihypertensive and alopecia medication. Much ofthe information regarding this drug is drawn from theliterature detailing its use in the former rather thanlatter circumstance.

Minoxidil is an antihypertensive agent while topicalminoxidil (Rogaine) is used for alopecia. Due to itspotency and adverse reactions, oral minoxidil is usedmainly for patients with the severe drug resistantforms of hypertension. Tolerance to a prolonged the-rapy with oral minoxidil does not appear to be a pro-blem. Subsequent to the oral dosage (approved bythe FDA in 1979 for use in hypertension) topical for-mulations were approved for the treatment of alope-cia in 1988. Investigation of topical formulations inthe treatment of erectile dysfunction are limited andfollow on the heels of its approval for alopecia.

Minoxidil does not have a direct vasodilatory effecton arterial smooth muscle. Rather, it is converted tominoxidil O-sulfate by the hepatic enzyme sulfo-transferase (McCall et al., 1983). This metabolitedoes have a direct vasodilatory effect on arterialsmooth muscle causing a reduction in peripheralresistance and blood pressure. While the precisemechanism of action of minoxidil is not certain

4.III. TOPICAL MINOXIDIL

4.II. TOPICAL PGE1

4.I. TOPICAL THERAPY FORERECTILE DYSFUNCTION –

BACKGROUND

524

(Quast et al., 1995; Russ et al., 2003), and moreover,may vary among distinct smooth muscle cell types(Buchheit et al., 2000; Davies et al., 1996), it clearlyappears to be a relatively weak corporal smoothmuscle cell relaxant (Christ, 1995). In that regard,minoxidil is not known to inhibit the CNS or haveadrenergic neuronal blocking effects. Minoxidilretains its activity despite adrenergic denervation.With respect to the mechanism of action, presumablyat least some aspects of minoxidil-induced relaxationshares common features with other members of theK channel modulator family (i.e., pinacidil, croma-kalim, etc.). In fact, in both vascular and nonvascu-lar (including urogenital) smooth muscle, minoxidiland other K channel activators have been shown toactivate KATP channels in a glibenclamide-sensitivefashion (Newgreen et al., 1990; Khan et al., 1997;Teramoto & Ito, 1999). In all these cases, activationof the KATP channel subtype results in an increasedK+ efflux and cellular hyperpolarization. The netresult is a physiological antagonism of transmembra-ne calcium flux through L-type voltage-dependentcalcium channels, a reduction in the free intracellularcalcium concentration, and a corresponding smoothmuscle cell relaxation.

With regards to the treatment of erectile dysfunction,it is assumed that the active metabolite acts via adirect vasodilatory effect on corporal and arterialsmooth muscle causing a reduction in peripheralresistance and cavernosal muscle relaxation. Presu-mably this promotes the veno-occlusive mechanismand results in erection. Such an effect from topicalminoxidil is interesting when one considers that it isa prodrug that requires hepatic metabolism to beco-me active (McCall et al., 1983). For this to be effec-tive the topically absorbed minoxidil would have tobe metabolized through the liver then recirculated tothe penis to be active. This appears to be a substan-tial task. Issues regarding the site and efficacy ofabsorption have been addressed above.

Topical administration of minoxidil solutions shouldonly be applied to the skin of interest. Absorption isbest when the hair and the skin are dry. If appliedwith finger tips the hands should be thoroughlywashed after applying. Systemic effects resultingfrom topically administered Minoxidil are unlikelybut theoretically could occur if the drug is overused.Skin abrasion or irritation such as excoriations, pso-riasis, or sun burn can increase the systemic absorp-tion of topical minoxidil.

Since the introduction by Virag in the early 1980s,injection of papaverine into the corporal bodies forthe treatment of sexual dysfunction has become awidespread and well accepted method (Virag, 1982).The use of papaverine as a topical therapy has amuch shorter experience and one that has not movedbeyond preliminary clinical trials.

The most characteristic effect of papaverine isrelaxation of smooth muscle, especially when it hasbeen spasmodically contracted. Papaverine acts, inlarge part, directly on the muscle itself. There may beseveral possible mechanisms by which papaverine isable to directly relax corporal smooth muscle, but themost prominent is by inhibition of the oxidativephosphorylation mediated inactivation of cAMP (viaphosphodiesterase-PDE) which interferes with cal-cium mobilization during muscle contraction. Infact, papaverine is a nonspecific phosphodiesteraseinhibitor that initiates an increase in intracellularcAMP and cGMP leading to corporal smooth musclerelaxation and penile erection; via prolongation ofthe half-life of these cyclic nucleotides. Papaverinemay also regulate cavernosal smooth muscle tone viainhibition of voltage-dependent L-type Ca2+ chan-nels independent of cAMP as demonstrated in tra-cheal smooth muscle and by suppression of angio-tensin II secretion in cavernosal tissue (Iguchi et al,1992; Kifor et al, 1997)

Serum papaverine levels after topical administrationhave been measured in a single study (Kim et al.,1995) with a high performance liquid chromatogra-phy assay. At 60 minutes mean serum levels increa-sed 50% suggesting that absorption did occur, butnot significantly over baseline values. The papaveri-ne levels in this study indicated that topical absorp-tion is less than 1% of a comparable intravenousdose indicating minimal systemic uptake after topi-cal administration to the genitalia. In contrast, papa-verine is present in the blood at levels of 335 to 761ng/ml within 3 minutes of IC injection of 40 mg asmeasured by similar techniques (Tanaka et al.,1990). The pharmacokinetics and bioavailability oftopical papaverine on animal models have been stu-died in which 9-12.4% of the papaverine is detectedin the serum. Why the marked differences betweenanimal models and clinical trials has been blamed ongel formulation (Shaaya et al., 1992).

4.IV. TOPICAL PAPAVERINE

525

The use of topical nitroglycerin is a standard treat-ment for unstable angina pectoris because predic-table blood levels can be achieved. The use of nitro-glycerin ointments, pastes, plasters or patches for thetreatment of erectile dysfunction has been tried inseveral studies (see earlier sections in this chapter).The putative mechanism of action is describedbelow.

Relaxation of corporal and arterial smooth muscle isthe principle pharmacologic action of nitroglycerin,and presumably is dependent on activation of theNO/guanylate cyclase/cGMP/Protein Kinase G path-way. Nitroglycerin produces, in a dose dependentmanner, dilation of both arterial and venous beds,dilatation of the post-capillary vessels includinglarge veins and decreases in venous return. Thisresults in a reduction of left ventricular diastolicpressure. Arteriolar relaxation reduces systemic vas-cular resistance and arterial pressure.

The mechanistic basis for nitroglycerine-inducedrelaxation of human corporal smooth muscle is like-ly to be multifactorial, but the contribution of themajor physiological entities seems quite clear. In thisregard, cellular metabolism of nitroglycerine to NOand subsequent activation of soluble guanlyatecyclase in the smooth muscle cell is the first step inthe process. Activation of guanylate cyclase resultsin formation of cGMP, which in turn activates pro-tein kinase G. Protein kinase G presumably phos-phorylates a variety of target proteins, such as Kchannels (KCa, KATP, Kv; see Irvine et al., 2003;

Archer, 2002; Bivalacqua et al., 2000; Lin et al.,2002; Lee & Kang, 2001; Spektor et al., 2002), L-Type calcium channels (Adachi et al., 2001), sarco-plasmic reticulum calcium pumps (SERCA; Adachiet al., 2001), and perhaps Rho kinase as well (Chita-ley et al., 2003). Moreover, there may well be asignificant cGMP-independent component to NO-mediated relaxation of smooth muscle (Adachi et al.,2001; Irvine et al., 2003). Virtually all of thesereports have emphasized the important impact of theNO signalling pathway to diminish the free intracel-lular calcium levels, as a major mechanism of theensuing NO-mediated relaxation response. Theseobservations are consistent with the importance ofreduced transmembrane calcium flux and/or increa-sed calcium sequestration/extrusion mechanisms to

nitroglycerine-induced relaxation. As indicatedabove, one major consensus point seems to be theimportant role played by K channel-mediated hyper-polarizing currents in this process. Furthermore,disease (diabetes)-related changes in the responsivi-ty of isolated human corporal smooth muscle stripsto nitroglycerine-induced relaxation may indicatethat this compound may have diminished utility indiabetic patients. Other contraindications to the useof topical nitroglycerin include those who have aller-gic reactions to organic nitrates. These are extremelyrare, but they do occur. Allergies to the adhesivesused within the nitroglycerin patches have also beenreported.

Adachi, T., Matsui, R., Weisbrod, R.M., Najibi, S., Cohen,R.A.: Reduced Sarco/Endoplasmic Reticulum Ca2+ Uptakeactivity can account for the reduced response to NO, but notsodium nitroprusside, in hypercholesterolemic rabbit aorta.Circ.104: 1040-1045, 2001.

Archer, S.L.: Potassium channels and erectile dysfunction.Vascul. Pharmacol. 38(1):61-71, 2002.

Becher E, Borghi M, Momesso A, et al: Penile hemodynamicfindings with a new topical formulation of alprostadil. J Urol,159 No5 Suppl: 239; 1998.

Bivalacqua, T.J., Champion, H.C., Purohit, S.K., Murphy,W.A., Coy, D.H., Kadowitz, P.J., Hellstrom, WayneJ.G.:Nitric Oxide-mediated erectile effects of galantide butNot Galanin in Vivo. Nitric Oxide: Biology and Chemistry.4(2):94-102, 2000.

Buchheit, K-H., Hofmann, A., Manley, P., Pfannkuche, H-J.:Atypical effect of minoxidil sulphate on guinea pig airways.Naunyn-Schmiedeberg’s Arch Pharmacol. 361:418-424,2000.

Cahn, D.J. Melman, A. Valcic, M. & Christ, G.J.: Forskolin:A promising new adjunct to intracavernous pharmacotherapy.J. Urol. 155:1789-1794, 1996.

Cavallini, G.: Minoxidil versus nitroglycerin: a prospectivedouble-blind controlled trial in transcutaneous erection facili-tation for organic impotence. J. Urol., 146: 50, 1991.

Chitaley, K., Webb., R.C., Mills, T.M.: The ups and downs ofRho-kinase and penile erection: upstream regulators anddownstream substrates of rho-kinase and their potenital rolein the erectile response. Int. J. of Impotence Res. 15:105-109,2003.

Christ, G.J., Kim, D.C., Taub, H.C., Gondre, M.C., Melman,A.: Characterization of nitroglycerine-induced relaxation inhuman corpus cavernosum smooth muscle: implications toerectile physiology and dysfunction. 73(12):1714-1726.1995.

REFERENCES

4.V. TOPICAL NITROGLYCERIN

526

Cellek, S., Rees, R.W., Kalsi, J.: A Rho-kinase inhibitor,soluble guanylate cyclase activator and nitric oxide-releasingPDE5 inhibitor: novel approaches to erectile dysfunction.Expert Opin. Investig. Drugs. 11(11):1563-1573. 2002.

Clark, R.V., Murray, F.T., Hirshkowitz, M., Ferry, J., Lin, T.,Murphy, T.C. and Francom, S.F.: Treatment of erectile dys-function in men with diabetes mellitus using a penetration-enhanced topical minoxidil solution. J. Andrology, Janua-ry/February supplement: abstract 140, p. 55, 1994.

Davies, M.P., McCurrie, J.R., Wood, D.: Comparative effectsof K+ channel modulating agents on contractions of rat intes-tinal smooth muscle. Europ. J. of Pharmacol. 297:249-256.1996.

Gurny R, Teubner A: Dermal and transdermal drug delivery:new insights and perspectives. Stuttgart: Wiss. Verl.-Ges.,1993.

Iguchi M, Nakajima T, Hisada T, Sugimoto T, Kurachi Y. Onthe mechanism of papaverine inhibition of the voltage-depen-dent Ca++ current in isolated smooth muscle cells from theguinea pig trachea. J Pharmacol Exp Ther 1992 ; 263(1): 194-200.

Irvine, J.C., Favaloro, J.L., Kemp-Harper, B.K.: No- acti-vates soluble guanylate cyclase and Kv channels to vasodila-te resistance arteries. Hypertension. 41:1301-1307, 2003.

Khan, S.A., Higdon, N.R., Hester, J.B., Meisheri, K.D.: Phar-macological characterization of Novel Cyanoguanidines asvascular KATP channel blockers. J. Pharmacol. Exp. Thera-

peutics. 283:1207-1213, 1997.

Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P,Dluhy RG. Tissue angiotensin II as a modulator of erectilefunction. I. Angiotensin peptide content, secretion and effectsin the corpus cavernosum. J Urol 1997; 157(5): 1920-5.

Kim ED, el-Rashidy R, Mc Vary KT: Papaverine topical gelfor treatment of erectile dysfunction. J Urol, 153:361-365;1995.

Lee SW, Wang HZ, Zhao W, Ney P, Brink PR, Christ GJ.Prostaglandin E1 activates the large-conductance KCa chan-

nel in human corporal smooth muscle cells. Int J Impot Res1999; 11(4): 189-99.

Lin JS, Lin YM, Jou YC, Cheng JT. Role of cyclic adenosinemonophosphate in prostaglandin E1-induced penile erectionin rabbits. Eur Urol 1995; 28(3): 259-65.

Lin, R-J., Wu, B-N., Lo, Y-C., Shen, K-P., Lin, Y-T., Huang,C-H., Chen, I-J.: KMUP-1 relaxes rabbit corpus cavernosumsmooth muscle in vitro and in vivo: involvement of cyclicGMP and K+ channels. Br. J. of Pharmacol. 135:1159-1166,2002.

Maibach, H.I., Feldman, R.J., Milby, T.H. and Serat, W.F.:Regional variation in percutaneous penetration in man. Arch.Environ. Health, 23: 208, 1971.

McCall, J. M., Aiken, J. W., Chidester, C. G., Du Charme, D.W., and Wendling, M. G. Pyrimidine and triazine 3-oxide sul-fates: a new family of vasodilators. J. Med. Chem, 1983, 26:1791-1793).

McVary KT, Polepalle S, Riggi S, Pelham RW. Topical pros-taglandin E1 SEPA gel for the treatment of erectile dysfunc-tion. J Urol. 1999 Sep;162(3 Pt 1):726-30.

Molderings GJ, van Ahlen H, Gothert M. Modulation of nora-drenaline release in human corpus cavernosum by presynap-tic prostaglandin receptors. Int J Impot Res 1992; 4: 19-25.

Moreland, R.B., Albadawi, H., Bratton, C., Patton, G., Gold-stein, I., Traish, A. and Watkins, M.T.: O2-dependent prosta-

noid synthesis activates functional PGE receptors on corpuscavernosum smooth muscle. Am. J. Physiol. 281: H552-H558, 2001.

Mudd. J.W.: Impotence responsive to glyceryl trinitrate.Amer. J. Psych., 134: 922, 1977.

Newgreen, D.T., Bray, K.M., McHarg, A.D., Weston, A.H.,Duty, S., Brown, B.S., Kay, P.B., Edwards, G., Longmore, J.,Southerton, J.S.: The action of diazoxide and minoxidil sul-phate on rat blood vessels: a comparison with cromakalim.Br. J. Pharmacol. 100(3):605-613. 1990.

Nunez BD, Anderson DC Jr: Nitroglycerin ointment in thetreatment of impotence. J Urol, 150:1241-1243; 1993.

Owen, J.A., Saunders, F., Harris, C., Fenemore, J., Reid, K.,Surridge, D., Condra, M. and Morales, A.: Topical nitrogly-cerin: a potential treatment for impotence. J. Urol., 141: 546,1989.

Palmer, L., Valcic, M., Melman, A., Giraldi, A., Wagner, G.,Melman, A. & Christ, G.J.: Characterization of cAMP accu-mulation in cultured human corpus cavernosum smoothmuscle cells. J. Urol. 152:1308-1314, 1994.

Pelham, R. and Samour, C. SEPA-009-Safety and EfficacyStudies of a Broad Spectrum Transdermal Enhancer. Proceed.Intern. Symp. Control. Rel. Bioact Mater., 22:694-695, 1995.

Quast, U., Baumlin, Y., Loffler, C.: Ba2+ differentially inhi-bits the Rb+ efflux promoting and the vasorelaxant effects oflevcromakalim and minoxidil sulfate in rat-isolated aorta.Naunyn Schmiedebergs Arch Pharmacol. 353:86-93. 1995.

Russ, U., Lange, U., Loffler-Walz, C., Hambrock, A., andQuast, U.: Binding and effect of Katp channel openers in theabsence of Mg2+. Br. J. Pharmacol. 139:368-380, 2003.

Samour, C.M., Donaruma, L.G., Daskalakis, S., Fulton, B.S.,Marty, J.P., Dervault, A.M., Chanez, J.F. and Doucet, O.SEPAs, A New Class of Percutaneous Absorption Enhancers.Proc. Intern. Symp. Control. Rel. Bioact Mater 16: 183-184,1989.

Shaaya, A.N. , Kraus, C., Bauman, D.H. and Ritschel, W.A.Pharmacokinetics and bioavailability of papavervine HClafter intervenous, intracorporeal and penis topical applicationin beagle dogs. Methods Findings Exp. Clin. Pharm., 14: 373,1992.

527

Spektor, M., Rodriquez, R., Rosenbaum, R.S., Wang, H-Z.,Melman, A., and Christ, G.J.: Potassium channels and humancorporeal smooth muuscle cell tone: Further evidence of thephysiological relevance of the max-K channel subtype to theregulation of human corporel smooth muscle tone in vitro. J.of Urology. 167:2628-2635, 2002.

Tanaka, T.: Papaverine hydrochoride in periphiral blood andthe degree of penile erection. J. Urol., 143: 1135, 1990.

Traish, A.M., Moreland, R.B., Gallant, C., Huang, Y.H. &Goldstein, I.: G-protein-coupled receptor agonists augmentadenylyl cyclase activity induced by forskolin in human cor-pus cavernosum smooth muscle cells. Recept. Signal Trans-duct. 7: 121-132, 1997.Teramoto, N., Ito, Y.: Comparative studies on the relaxingaction of several adenosine 5’-triphosphate-sensitive K+channel openers in pig urethra. J. Smooth Muscle Res.35(1):11-22. 1999.Virag, R.: Intracavernous injection of papaverine for erectilefailure. Letter to the Editor, Lancelet, 2: 938, 1982.Wolfson, B., Pickett, S., Scott, N.E., DeKernion, J.B. and Raj-fer, J.: Intraurethral prostaglandin E-2 cream: a possible alter-native treatment for erectile dysfunction. Urology, 42: 73,1993

528

Qualifications for review by the committee

Peer-reviewed scientific publications

Over 700 papers reviewed and graded

Publications: 1995-2004 (first part of 2004) (in press included)

Excluded:

Abstracts

Case studies

Review articles

Papers in journal supplements

1. GRADING THE LEVEL OF EVIDENCE

• High (level 1)

High quality RCT with high power

• Intermediate (level 2)

RCT with low power and/or less than 80% follow-upand retention

Good quality, non-randomized, prospective compa-rative study

Low (level 3)

Uncontrolled studies

Non-randomized comparative studies with historicalcontrol

2. CATAGORIES FOR GROUPING OF PUBLICA-TION REVIEWS

General Efficacy

Special Population Efficacy

General and Class Specific Safety

Cardiovascular Investigations

1. GENERAL EFFICACY

Ten (10) level 1 publications [1-10], three (3) level 2 publications [11-13], and twenty two (22) level 3 publications [14-35].

2. SPECIAL POPULATION EFFICACY

• Diabetic ED Patients

Three (3) level 1 publications [36,37, 150], one (1) level 2 publications [38], and two (2) level 3 publication [24, 39].

• Patients with Cardiovascular Disease (CAD,hypertension) and ED

Two (2) level 1 [40] and two (2) level 2 publications [41, 42].

• Post-Prostatectomy ED Patients

Seven (7) level 3 publications [43-49].

• SSRI- Related ED Patients

One (1) level 1 [50], one level 2 [51]and three (3) level 3 publications [52-54]

• Depression-related ED Patients

Two (2) level 1 [50, 55]and one (1) level 3 publications [56]

• Spinal Injury-related ED Patients

Two (2) level 1 publications from a single trial[57, 58], two (2) level 2 publications from a single trial[59, 60] and three (3) level 3 publications [61-63].

• Radiation Therapy-related ED Patients

One (1) level 2 [64]and eight (8) level 3 publications [65-72].

• Spina Bifida ED Patients

One (1) level 2 [73]

• Intracavernosal Injection Therapy FailurePatients

One (1) level 3 publication [74]

• Psychiatric Outpatients with ED

One (1) level 3 publication [75]

1. PDE5 INHIBITORS: SILDENAFIL

II. ORAL ED PHARMACOTHERAPIES

I. INTRODUCTION

B. EVIDENCE-BASED REVIEWOF ED PHARMCOTHERAPIES

529

530

Det

aile

d re

view

of

impo

rtan

t Sild

enaf

il cl

inic

al p

ublic

atio

ns

531

Det

aile

d re

view

of

impo

rtan

t Sild

enaf

il cl

inic

al p

ublic

atio

nsE

FD

= E

rect

ile F

unct

ion

Dom

ain

Scor

e.

GA

Q:

Glo

bal A

sses

smen

t Que

stio

n :

has

the

trea

tmen

t you

hav

e be

en ta

king

ove

r th

e pa

st 4

wee

ks im

prov

ed

your

ere

ctio

n ?

532

Det

aile

d re

view

of

impo

rtan

t Sild

enaf

il cl

inic

al p

ublic

atio

ns

Tab

le 3

: A

dve

rse

even

ts (

AE

) an

d C

om

men

ts

533

Det

aile

d re

view

of

impo

rtan

t Sild

enaf

il cl

inic

al p

ublic

atio

ns

• Parkinson’s Disease ED Patients

One (1) level 2 [76] and two (2) level 3 publications [77, 78]

• Psychotropic Medication Related ED PatientsOne (1) level 3 publication [79]

• Renal Failure Patients on Dialysis with ED

Six (6) level 3 publications [80-85]

• The Elderly ED Patients

One (1) level 2 [86] and one (1) level 3 publication [21]

• Chemotherapy and Testosterone Treated EDPatient

One (1) level 3 publication [87]

• Post-radical Proctectomy related ED Patients

One (1) level 2 publications [88]

• Post-renal Transplant Patients with ED

Two (2) level 3 publications [89, 90].

3. GENERAL AND CLASS SPECIFIC SAFETY ISSUES

Nineteen (19) level 1 [1-9, 36, 37, 40, 50, 55, 57,91-93, 150], six (6) level 2 [13, 41, 51, 94-96], and twenty three (23) level 3 publications [14-17,19-27, 31-35, 97-101]. This category includes studies related to ocularsafety

4. Cardiovascular Investigations

Thirty (30) level 1 [36, 40, 41, 94, 102-127], twenty three (23) level 2 [96, 128-149]

1. Goldstein I, Lue T, Padma-Nathan H, Rosen R, Steers W,Wicker P for the Sildenafil Study Group. Oral sildenafilin the treatment of erectile dysfunction. N Engl J Med1998; 338:1397-1404.

2. Padma-Nathan H. Efficacy and safety of oral sildenafil inthe treatment of erectile dysfunction: a double-blind, pla-cebo-controlled study of 329 patients. Int J Clin Prac1998; 52:1-5

3. Dinsmore W, Hodges M, Hargreaves C, Osterloh I,Smith M, Rosen R. Sildenafil citrate (Viagra) in erectiledysfunction: near normalization in men with broad-spec-trum erectile dysfunction compared with age-matched,healthy control subjects. Urology 1999;53(4): 800-5.

4. Montorsi F, McDermott TED, Morgan R, Olsson A,Schultz A, Kirkeby HJ, Osterloh IH. Efficacy and safetyof fixed-dose oral sildenafil in the treatment of erectiledysfunction of various etiologies. Urology 1999; 53:

1011-8

5. Tan HM, Moh CLC, Mendoza JB, Gana T Jr, Albano GJ,de la Cruz R, Chye PLH, Sam CCW, ASSESS-1 StudyGroup. Asian sildenafil efficacy and safety study(ASSESS-1): A double-blind, placebo-controlledflexible-dose study of oral sildenafil in Malaysian, Sin-gaporean, and Filipino men with erectile dysfunction.Urology 2000;56:635-640

6. Christiansen E, Guirguis WR, Cox D, Osterloh IH for theSildenafil Multicenter Study Group. Long-term efficacyand safety of oral VIAGRA (sildenafil citrate) in menwith erectile dysfunction and the effect of randomisedtreatment withdrawal. Int J Impot Res 2000;12:177-182.

7. Olsson AM, Speakman MJ, Dinsmore WW, Giuliano F,Gingell C, Maytom M, Smith MD, Osterloh I. Sildena-fil citrate (VIAGRA) is effective and well tolerated fortreating erectile dysfunction of psychogenic or mixedaetiology. Int J Clin Pract 2000;54(9):561-566

8. Meuleman E, Cuzin B, Opsomer RJ, Hartmann U, Bai-ley MJ, Maytom MC, Smith MD, Osterloh IH. A dose-escalation study to assess the efficacy and safety of sildenafil citrate in men with erectile dysfunction. BJUInt. 2001;87(1):75-81

9. Chen KK, Hsieh JT, Huang ST, Jiaan DBP, Lin JSN,Wang CJ, for the Assess 3 Study Group. ASSESS-3: arandomised, double-blind, flexible-dose clinical trial ofthe efficacy and safety of oral sildenafil in the treatmentof men with erectile dysfunction in Taiwan. Int J ImpotRes. 2001;13 :221-229

10. Giuliano F, Pena BM, Mishra A, Smith MD. Efficacyresults and quality-of-life measures in men receiving sil-denafil citrate for the treatment of erectile dysfunction.Qual Life Res. 2001;10(4):359-369

11. Boolell M, Allen M, Ballard S, Gepi-Attee S, MuirheadG, Naylor A, Osterloh I, Gingell C. Sildenafil: an orallyactive type 5 cyclic GMP-specific phosphodiesteraseinhibitor for the treatment of penile erectile dysfunction.Int J Impot Res 1996;47-52

12. Boolell M, Gepi-Attee S, Gingell C, Allen M. Sildena-fil: a novel effective oral therapy for male erectile dys-function. Br J of Urol 1996;78:257-261

13. Eardley I, Morgan R, Dinsmore W, Yates P, Boolell M.Efficacy and safety of sildenafil citrate in the treatmentof men with mild to moderate erectile dysfunction. Br JPsychiatry. 2001, 178(4):325-330

14. Marks LS, Duda C, Dorey FJ, Macairan ML, Santos PB.Treatment of erectile dysfunction with sildenafil. Urolo-gy 1999 Jan;53(1):19-24

15. Jarow JP, Burnett AL, Geringer AM. Clinical efficacy ofsildenafil citrate based on etiology and response to priortreatment. J Urol Sep 1999;162:722-725

16. Virag R. Indications and early results of sildenafil (Via-gra®) in erectile dysfunction. Urology 1999;54(6):1073-7

17. Giuliano F, Montorsi F, Mirone V, Rossi D, Sweeney M.Switching from intracavernous prostaglandin E1 injec-tions to oral sildenafil citrate in patients with erectiledysfunction: results of a multicenter European study. JUrol 2000;164:708-711

18. Hatzichristou DG, Apostolidis A, Tzortzis V, Ioannides

SIDENAFIL REFERENCES

534

E, Yannakoyorgos K, Kalinderis A. Sildenafil versusintracavernous injection therapy: efficacy and preferencein patients on intracavernous injection for more than 1year. J Urol 2000, 164:1197-120.

19. Palumbo F, Bettocchi C, Selvaggi FP, Pryor JP, RalphDJ. Sildenafil: efficacy and safety in daily clinical expe-rience. Eur Urol. 2001;40(2):176-180

20. Gil A, Martinez E, Oyaguez I, Palacios G, Rejas J. Erec-tile dysfunction in a primary care setting: results of anobservational, no-control-group, prospective study withsildenafil under routine conditions of use. Int J ImpotRes. 2001; 13338-347.

21. Tsujimura A, Yamanaka M, Takahashi T, Miura H, Nishi-mura K, Koga M, Iwasa A, Takeyama M, Matsumiya K,Takahara S, Okuyama A. The clinical studies of sildena-fil for the ageing male. Int J Androl. 2002 Feb;25(1):28-33

22. Guay AT, Perez JB, Jacobson J, Newton RA. Efficacyand safety of sildenafil citrate for treatment of erectiledysfunction in a population with associated organic riskfactors. J Androl. 2001; 22:793-797

23. Lim PH, Li MK, Ng FC, Chia SJ, Consigliere D, GoorenL, Ng KK, Munisamy M, Perianan M.Clinical efficacyand safety of sildenafil citrate (Viagra) in a multi-racialpopulation in Singapore: A retrospective study of 1520patients. Int J Urol. 2002 ; 9(6):308-315

24. Ng KK, Lim HCP, Ng FC, Li MK, Consigliere D, ChiaSJ. The use of sildenafil in patients with erectile dys-function in relation to diabetes mellitus – a study of 1,511patients. Singapore Med J. 2002;43(8):387-390

25. Paige NM, Hays RD, Litwin MS, Rajfer J, Shapiro MF.Improvement of emotional well-being and relationshipsof users of sildenafil. J Urol. 2001, 166(5):1774-1778

26. Fujisawa M, Sawada K, Okada H, Arakawa S, Saito S,Kamidono S. Evaluation of health-related quality of lifein patients treated for erectile dysfunction with VIAGRA(sildenafil citrate) using SF-36 score. Arch Androl. 2002

27. McMahon CG, Samali R, Johnson H. Efficacy, safety,and patient acceptance of sildenafil citrate as treatmentfor erectile dysfunction. J Urol 2000; 164:1192-1196

28. Moser C. The effect of sildenafil citrate on middle-aged«normal» men. Elect J Human Sexuality. 2001;Vol4:www.ejhs.org.

29. Terradas C, Levalle O, Nagelberg A, Mormandi E. Silde-nafil improves nocturnal penile erections in organicimpotence. Int J Impot Res. 2001;13(2):125-129

30. Huang ST. Use of sildenafil citrate in treatment of Tai-wanese men with erectile dysfunction: a single centerexperience. Chang Gung Med J. 2001, 24: 91-96

31. El-Galley R, Rutland H, Talic R, Keane T, Clark H.Long-term efficacy of sildenafil and tachyphylaxis effectJ Urol. 200; 166: 927-931

32. Grass H, Koltz T, Fathian-Sabet B, Berghaus G, Engel-mann U, Kaferstein H Sildenafil (Viagra): is there aninfluence on psychological performance? Int UrolNephrol. 200; 32: 409-412

33. Basar M, Tekdogan UY, Yilmaz E, Basar H, Atan A,Batislam E. The efficacy of sildenafil in different etiolo-

gies of erectile dysfunction. Int Urol Nephrol, 2001; 32:403-407

34. Muller MJ, Benkert O. Lower self-reported depression inpatients with erectile dysfunction after treatment with sil-denafil. J Affect Disord. 2001; 66: 255-261

35. Chen J, Mabjeesh NJ, Greenstein A. Sildenafil versusthe vacuum erection device: patient preference. J Urol.2001; 166: 1779-1781

36. Rendell M, Rajfer J, Wicker P, Smith M, Sildenafil Dia-betes Study Group. Sildenafil for treatment of erectiledysfunction in men with diabetes: a randomized controltrial. JAMA, 1999; 281: 421-426

37. Boulton AJM, Selam JL, Sweeney M, Ziegler D. Silde-nafil for the treatment of erectile dysfunction in men withtype II diabetes mellitus. Diabetologia. 2001; 44:1296-1301.

38. Price D, Boolell M, Gepi-Attee S, Wareham K, Yates P,Gingell J. Sildenafil: study of a novel oral treatment forerectile dysfunction in diabetic men. Diabet Med 1998;15: 821-825

39. Perimenis P, Markou S, Gyftopoulos K, AthanasopoulosA, Giannitsas K, Barbalias G. Switching from long-termtreatment with self-injections to oral sildenafil in diabe-tic patients with severe erectile dysfunction. EuropeanUrology 2002:41: 387-391.

40. Olsson AM, Persson C-A. Efficacy and safety of silde-nafil citrate for the treatment of erectile dysfunction inmen with cardiovascular disease. Int J Clin Prac. 2001;55: 171-176.

41. Kloner R, Brown M, Prisant LM, Collins M, for the Sil-denafil Study Group. Effect of sildenafil in patients witherectile dysfunction taking antihypertensive therapy. AmJ Hypertens. 2001; 14: 70-73

42. Bocchi EA, Guimaraes G, Mocelin A, Bacal F, BellottiG, Ramires JF. Sildenafil effects on exercise, neurohor-monal activation, and erectile dysfunction in congestiveheart failure: a double-blind, placebo-controlled, rando-mized study followed by a prospective treatment forerectile dysfunction. Circulation. 2002; 106: 1097-103.

43. Zippe CD, Jhaveri JM, Klein EA, Kedia S, PasqualottoFF, Kedia A, Agarwal A, Montague DK, Lakin AM. Roleof Viagra® after radical prostatectomy. Urology 2000;55: 241-245.

44. Zippe C, Kedia A, Kedia K, Nelson D, Agarwal A. Treat-ment of erectile dysfunction after radical prostatectomywith sildenafil citrate (VIAGRA™). Urology 1998; 52:963-966

45. Lowentritt BH, Scardino PT, Miles BJ, Orejuela FJ,Schatte EC, Slawin KM, Elliote SP, Kim ED. Sildenafilcitrate after radical retropubic prostatectomy. J Urol1999; 162:1614-1617.

46. Zagaja GP, Mhoon DA, Aikens JE, Brendler CB. Silde-nafil in the treatment of erectile dysfunction after radicalprostatectomy. Urology 2000;56:631-634.

47. Blander DS, Sanchez-Ortiz RF, Wein AJ, Broderick GA.Efficacy of sildenafil in erectile dysfunction after radicalprostatectomy. Int J Impot Res 2000;12:165-168

48. Feng MI, Huang S, Kaptein J, Kaswick J, Aboseif S.Effect of sildenafil citrate on post-radical prostatectomy

535

erectile dysfunction. J Urol 2000; 164: 1935-1938

49. Baniel J, Israilov S, Segenreich E, Livne PM. Compara-tive evaluation of treatments for erectile dysfunction inpatients with prostate cancer after radical retropubicprostatectomy. BJU Int. 2001; 88: 58-62

50. Nurnberg HG. Hensley PL. Gelenberg AJ. Fava M. Lau-riello J. Paine S. Treatment of antidepressant-associatedsexual dysfunction with sildenafil: a randomized control-led trial. JAMA. 2003; 289: 56-64

51. Nurnberg HG, Gelenberg A, Hargreave TB, HarrisonWM, Siegel RL, Smith MD Efficacy of sildenafil citratefor the treatment of erectile dysfunction in men takingserotonin reuptake inhibitors. Am J Psychiatry. 2001;158: 1926-1928.

52. Fava M, Rankin M, Alpert J, Nierenberg A, WorthingtonJ. An open trial of oral sildenafil in antidepressant-indu-ced sexual dysfunction. Psychotherapy & Psychosoma-tics 1998; 67:328-331.

53. Nurnberg HG, Lauriello J, Hensley PL, Parker LM,Keith SJ. Sildenafil for iatrogenic serotonergic antide-pressant medication-induced sexual dysfunction in 4patients. J Clin Psychiatry 1999 Jan; 60(1):33-5.

54. Reznik I, Zemishlany Z, Kotler M, Spivak B, WeizmanA, Mester R. Sildenafil Citrate for the Sexual Dysfunc-tion in Antidepressant-Treated Male Patients with Post-traumatic Stress Disorder. Psychother Psychosom. 2002;71: 173-176.

55. Seidman SN, Roose SP, Menza MA, Shabsigh R, RosenRC. Treatment of erectile dysfunction in men withdepressive symptoms: results of a placebo-controlledtrial with sildenafil citrate. Am J Psych. 2001; 158:1623-1630.

56. Wilson SA. Sildenafil improved erectile dysfunction andquality of life in men with co-morbid mild-to-moderatedepression. ACP J Club. 2002; 137: 21

57. Giuliano F, Hultling C, El Masry WS, Smith M, OsterlohI, Orr M, Maytom M, for the Sildenafil Study Group.Randomized trial of sildenafil for the treatment of erecti-le dysfunction in spinal cord injury. Annals of Neurolo-gy 1999; 46: 15-21

58. Hultling C, Giuliano F, Quirk F, Pena B, Mishra A, SmithD. Quality of life in patients with spinal cord injuryreceiving Viagra (sildenafil citrate) for the treatment oferectile dysfunction. Spinal Cord 2000; 38: 363-370.

59. Derry F, El Masry W, Hultling C, Maytom M, Orr M,Osterloh I, Smith M. Efficacy and safety of oral sildena-fil (VIAGRA™) in men with erectile dysfunction causedby spinal cord injury. Neurology 1998; 51: 1629-1633

60. Maytom M, Derry FA, Dinsmore WW, Glass CA, SmithMD, Orr M, Osterloh IH. A two-part pilot study of silde-nafil (VIAGRA™) in men with erectile dysfunction cau-sed by spinal cord injury. Spinal Cord 1999; 37: 110-6

61. Sánchez Ramos A, Vidal J, Jáuregui ML, Barrera M,Recio C, Giner M, Toribio L, Salvador S, Sanmartin A,de la Fuente M, Santos JF, de Juan FJ, Moraleda S, Men-dez JL, Ramirez L, Casado RM. Efficacy, safety and pre-dictive factors of therapeutic success with sildenafil forerectile dysfunction in patients with different spinal cordinjuries. Spinal Cord. 2001; 39: 637-643

62. Schmid DM, Schurch B, Hauri D. Sildenafil in the treat-ment of sexual dysfunction in spinal cord-injured malepatients. Eur Urol 2000; 38: 184-193

63. Gans WH, Zaslau S, Wheeler S, Galea G, Vapnek JM.Efficacy and safety of oral sildenafil in men with erecti-le dysfunction and spinal cord injury. J Spinal Cord Med.2001; 24: 35-40

64. Incrocci L, Koper PCM, Hop WCJ, Slob AK. Sildenafilcitrate (Viagra) and erectile dysfunction following exter-nal beam radiotherapy for prostate cancer: a randomized,double-blind, placebo-controlled, cross-over study. Int JRadiat Oncol Bio Phys. 2001; 51: 1190-1195

65. Potters L, Torre T, Fearn PA, Leibel SA, Kattan MW.Potency after permanent prostate brachytherapy for loca-lized prostate cancer. Int J Radiat Oncol Biol Phys.2001; 50 : 1235-1242

66. Zelefsky M, McKee A, Lee H, Leibel S. Efficacy of oralsildenafil in patients with erectile dysfunction afterradiotherapy for carcinoma of the prostate. Urology1999; 53: 775-8.

67. Merrick GS, Butler WM, Lief JH, Stipetich RL, Abel LJ,Dorsey AT. Efficacy of sildenafil citrate in prostate bra-chytherapy patients with erectile dysfunction. Urology1999; 53: 1112-1116

68. Kedia S, Zippe CD, Agarwal A, Nelson DR, Lakin MM.Treatment of erectile dysfunction with sildenafil citrate(Viagra) after radiation therapy for prostate cancer. Uro-logy 1999; 54: 308-312

69. Weber DC, Bieri S, Kurtz JM, Miralbell R. Prospectivepilot study of sildenafil for treatment of postradiotherapyerectile dysfunction in patients with prostate cancer JClin Oncol 1999; 17: 3444-3449

70. Valicenti RK, Choi E, Chen C, Lu JD, Hirsch IH, Mul-holland GS, Gomella LG Sildenafil citrate effectivelyreverses sexual dysfunction induced by three-dimensio-nal conformal radiation therapy. Urology. 2001; 57: 769-773

71. Merrick GS, Butler WM, Galbreath RW, Stipetich RL,Abel LJ, Lief JH. Erectile function after permanent pros-tate brachytherapy. Int J Radiat Oncol Biol Phys2002; 52: 893-902

72. Merrick GS, Wallner K, Butler WM, Lief JH, Sutlief S.Short-term sexual function after prostate brachytherapy.Int J Cancer. 2001; 96: 313-319.

73. Palmer JS, Kaplan WE, Firlit CF. Erectile dysfunction inspina bifida is treatable. Lancet 1999; 354: 125-6

74. McMahon CG, Samali R, Johnson H. Treatment of intra-corporeal injection nonresponse with sildenafil alone orin combination with triple agent intracorporeal injectiontherapy. J Urol 1999; 162: 1992-8.

75. Pallas J, Levine SB, Althof SE, Risen CB. A study usingViagra® in a mental health practice. J Sex Marital Ther2000; 26: 41-50.

76. Hussain IF, Brady CM, Swinn MJ, Mathias CJ, FowlerCJ. Treatment of erectile dysfunction with sildenafilcitrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations onorthostatic hypotension. J Neurol Neurosurg Psychiatry.2001; 71: 371-4.

536

77. Zesiewicz TA, Helal M, Hauser RA. Sildenafil citrate(Viagra®) for the treatment of erectile dysfunction inmen with Parkinson’s disease. Mov Disord 2000; 15:305-8

78. Raffaele R, Vecchio I, Giammusso B, Morgia G, Brunet-to MB, Rampello L. Efficacy and safety of fixed-doseoral sildenafil in the treatment of sexual dysfunction indepressed patients with idiopathic Parkinson’s disease.European Urology 2002;41: 382-386

79. Salerian AJ, Deibler WE, Vittone BJ, Geyer SP, Drell L,Mirmirani N, Mirczak JA, Byrd W, Tunick SB, Wax M,Fleisher S. Sildenafil for psychotropic-induced sexualdysfunction in 31 women and 61 men.J Sex Marital Ther2000; 26: 133-40.

80. YenicerioGlu Y, Kefi A, Aslan G, Cavdar C, Esen AA,Camsari T, Celebi I. Efficacy and safety of sildenafil fortreating erectile dysfunction in patients on dialysis. BJUInt. 2002; 90: 442-445.

81. Türk S, Karalezli G, Tonbul HZ, Yildiz M, Altintepe L,Yildiz A, Yeksan M. Erectile dysfunction and the effectsof sildenafil treatment in patients on haemodialysis andcontinuous ambulatory peritoneal dialysis. Nephrol DialTransplant. 2001; 16: 1818-1822.

82. Rosas SE, Wasserstein A, Kobrin S, Feldman HI. Preli-minary observations of sildenafil treatment for erectiledysfunction in dialysis patients. Am J Kidney Dis. 2001;37: 134-137

83. Chen J, Mabjeesh NJ, Greenstein A, Nadu A, Matskin H.Clinical efficacy of sildenafil in patients on chronic dia-lysis. J Urol. 2001; 165: 819-821

84. Punzo G, Maggi S, Ponzio R, Costarella M, Gentile V.Use of sildenafil in the chronic uraemic patient. MinervaUrol Nefrol. 2001; 53: 39-43

85. Juergense PH, Botev R, Wuerth D, Finkelstein SH,Smith JD, Finkelstein SO. Erectile dysfunction in chro-nic peritoneal dialysis patients: incidence and treatmentwith sildenafil. Perit Dial Int. 2001; 21: 355-359

86. Wagner G, Montorsi F, Auerbach S, Collins M. Sildena-fil citrate (Viagra) improves erectile function in elderlypatients with erectile dysfunction: a subgroup analysis. JGerontol A Biol Sci Med Sci. 2001; 56A: M113-M119.

87. Chatterjee R, Kottaridis PD, McGarrigle HH, Linch DC.Management of erectile dysfunction by combination the-rapy with testosterone and sildenafil in recipients ofhigh-dose therapy for haematological malignancies.Bone Marrow Transplant 2002; 29: 607-610

88. Lindsey I, George B, Kettlewell M, Mortensen N. Ran-domized, double-blind, placebo-controlled trial of silde-nafil (Viagra) for erectile dysfunction after rectal exci-sion for cancer and inflammatory bowel disease. DisColon Rectum. 2002; 45: 727-732.

89. Espinoza R, Melchor JL, Gracida C. Sildenafil (viagra)in kidney transplant recipients with erectile dysfunction.Transplantation Proc. 2002; 34: 408-9

90. Prieto Castro RM, Anglada Curado FJ, Requeiro LópezJC, Leva Vallego ME, Molina Sánchez J, Saceda LópezJL, Requena Tapia MJ. Treatment with sildenafil citratein renal transplant patients with erectile dysfunction.BJU Int. 2001; 88: 241-243

91. Lewis R, Bennett CJ, Borkon WD, Boykin WH, AlthofSE, Stecher VJ, Siegel RL. Patient and partner satisfac-tion with Viagra (sildenafil citrate) treatment as determi-ned by the erectile dysfunction inventory of treatmentsatisfaction questionnaire. Urology. 2001; 57: 960-965

92. Glina S, Bertero E, Claro J, Damião R, Faria G, Frego-nesi A, Jaspersen J, Mendoza A, Mattos Jr D, Rocha LC,Sotomayor M, Telõken C, Ureta S, Zonana E, Ugarte F.Efficacy and safety of sildenafil citrate for the treatmentof erectile dysfunction in Latin America. Braz J Urol.2001; 27: 148-154

93. Lim PH, Ng FC, Cheng CW, Wong MY, Chee CT, Moor-thy P, Vasan SS. Clinical safety profile of sildenafil inSingaporean men with erectile dysfunction: pre-marke-ting experience (ASSESS-I evaluation). J Int Med Res.2002; 30: 137-143

94. Morales A, Gingell C, Collins M, Wicker PA, OsterlohIH. Clinical safety of oral sildenafil citrate (Viagra) inthe treatment of erectile dysfunction. Int J Impot Res1998; 10: 69-74

95. Grunwald JE, Siu KK, Jacob SS, Dupont J. Effect of sil-denafil citrate (Viagra) on the ocular circulation. Am JOphthalmol. 2001; 131: 751-755.

96. Steers W, Guay AT, Gingell C, Hargreave TB, Wright PJ,Price DE, Feldman RA. Assessment of the efficacy andsafety of VIAGRA (sildenafil citrate) in men with erecti-le dysfunction during long-term treatment. Int J ImpotRes. 2001, 13: 261-267.

97. Moreira SG, Brannigan RE, Spitz A, Orejuela FJ, Lip-shultz LI, Kim ED. Side-effect profile of sildenafil citra-te (Viagra) in clinical practice. Urology 2000; 56: 474-6

98. Fagelman E, Fagelman A, Shabsigh R. Efficacy, safety,and use of sildenafil in urologic practice. Urology. 2001;57: 1141-1144

99. Martinez-Jabaloyas JM, Gil-Salom M, Villamón-Fort R,Pastor-Hernández F, Martinez-Garcia R, Garcia-SisamónF. Prognostic factors for response to sildenafil in patientswith erectile dysfunction. Eur Urol. 2001; 40: 641-647

100 McCulley TJ, Lam BL, Marmor MF, Hoffman KB, LuuJK, Feuer WJ. Acute effects of sildenafil (viagra) onblue-on-yellow and white-on-white Humphrey perime-try. J Neuroophthalmol 2000; 20: 227-228

101. Pache M, Meyer P, Prunte C, Orgul S, Nuttli I, FlammerJ. Sildenafil induces retinal vasodilatation in healthy sub-jects. Br J Ophthalmol. 2002; 86: 156-158.

102. Patrizi R, Leonardo F, Pelliccia F, et al. Effect of silde-nafil citrate upon myocardial ischemia in patients withchronic stable angina in therapy with beta-blockers. ItalHeart J 2001 ; 2(11):841-844.

103. Sugiyama A, Satoh Y, Shiina H, et al Cardiac electro-physiologic and hemodynamic effects of sildenafil, aPDE5 inhibitor, in anesthetized dogs. Journal of Cardio-vascular Pharmacology 2001; 38:940-946

104. Fagan TC, Buttler S, Marbury T, et al. Cardiovascularsafety of sublingual apomorphine in patients on stabledoses of oral antihypertensive agents and nitrates. Am JCardiol 2001; 88:760-766

105. Zhao L, Mason NA, Morrell NW, et al Sildenafil inhi-bits hypoxia-induced pulmonary hypertension. Circula-tion 2001; 104:424-428

537

106. Shakir SA, Wilton LV, Boshier A, et al. Cardiovascularevents in users of sildenafil: results from first phase ofprescription event monitoring in England. BMJ 2001;322:651-652

107. Zusman RM, Prisant LM, Brown MJ. Effect of sildena-fil citrate on blood pressure and heart rate in men witherectile dysfunction taking concomitant antihypertensivemedication. Journal of Hypertension 2000; 18:1865-1869

108. Przyklenk K, Kloner RA. Sildenafil citrate (Viagra)does not exacerbate myocardial ischemia in caninemodels of coronary artery stenosis. J Am Coll Cardiol200; 37:286-292

109. Traverse JH, Chen YJ, Du R, et al. Cyclic nucleotidephosphodiesterase type 5 activity limits blood flow tohypoperfused myocardium during exercise. Circulation2000; 102:2997-3002

110. Ishikura F, Beppu S, Hamada T, et al. Effects of silde-nafil citrate (Viagra) combined with nitrate on the heart.Circulation 2000; 102:2516-2521

111. Chen Y, Du R, Traverse JH, et al. Effect of sildenafil oncoronary active and reactive hyperemia.Am J PhysiolHeart Circ Physiol 2000; 279:H2319-2325.

112. Katz, SD, Balidemaj K, Homma S, et al. Acute type 5phosphodiesterase inhibition with sildenafil enhancesflow-mediated vasodilation in patients with chronic heartfailure.J Am Coll Cardiol 2000; 36:845-851.

113. Webb DJ, Muirhead GJ, Wulff M, et al. Sildenafil citra-te potentiates the hypotensive effects of nitric oxidedonor drugs in male patients with stable angina.J AmColl Cardiol 2000; 36:25-31.

114. Hermann HC, Chang G, Klugherz BD, et al. Hemodyna-mic effects of sildenafil in men with severe coronaryartery disease. N Engl J. Med 2000; 342:1622-1626

115. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil fortreatment of lung fibrosis and pulmonary hypertension: arandomised controlled trial. Lancet 2002; 360:895-900.

116. Kleinsasser A, Loeckinger A, Hoermann C, et al. Silde-nafil modulates hemodynamics and pulmonary gasexchange.Am J Respir Crit Care Med 2001; 163:339-343.

117. Ockaili R, Salloum F, Hawkins J, et al. Sildenafil (Via-gra) induces powerful cardioprotective effect via ope-ning of mitochondrial KATP channels in rabbits. Am JPhysiol Heart Circ Physiol 2002; 283:H1263-H1269.

117. Lepore JJ, Maroo A, Pereira NL. Effect of sildenafil onthe acute pulmonary vasodilator response to inhalednitric oxide in adults with primary pulmonary hyperten-sion. Am J Cardiol 2002; 90:677-680.

118. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafilis an effective and specific pulmonary vasodilator inpatients with pulmonary arterial hypertension. Circula-tion 2002; 105:2398-2403.

119. Welmann J, Ullrich R, Hromi J, et al. Sildenafil is a pul-monary vasodilator in awake lambs with acute pulmona-ry hypertension. Anesthesiology 2000; 92:1702-1712.

120. Bocchi EA, Guimarães G, Mocelin A, et al. Sildenafileffects on exercise, neurohormonal activation, and erec-

tile dysfunction in congestive heart failure. Circulation2002; 106:1097-1103.

121. Shekerdemian L, Ravn HB, Penny DJ. Intravenous sil-denafil lowers pulmonary vascular resistance in a modelof neonatal pulmonary hypertension. Am J Respir CritCare Med 2002; 165:1098-1102.

122. Vardi Y, Klein L, Nassar S, et al. Effects of sildenafilcitrate (Viagra) on blood pressure in normotensive andhypertensive men. Urology 2002; 59:747-752.

123. Ghofrani HA, Wiedemann R, Rose F, et al. Combinationtherapy with oral sildenafil and inhaled iloprost for seve-re pulmonary hypertension. Ann Intern Med. 2002;136:515-522.

124. Halcox JPJ, Nour KRA, Zalos G, et al. The effect of sil-denafil on human vascular function, platelet activation,and myocardial ischemia. J Am Coll Cardiol 2002;40:1232-1240.

125. Arruda-Olson AM, Mahoney DW, Nehra A, et al. Car-diovascular effects of sildenafil during exercise in menwith known or probable coronary artery disease. JAMA2002; 287:719-725.

126. Chiang C-E, Luk H-N, Wang T-M, Ding P Y-A. Effectsof sildenafil on cardiac repolarization. CardiovascularRes 2002; 55:290-299.

127. Desouza C, Parulkar A, Lumpkin D, et al. Acute andprolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care2002; 25:1336-1339.

128. Agelink MW, Schmitz T, Rembrink K, et al Cardiovas-cular effects of sildenafil citrate (Viagra“): A naturalisticcross-over study. Eur J Med Res 2001 6:459-564.

129. Mahmud A, Hennessy M, and Feely J. Effect of silde-nafil on blood pressure and arterial wave reflection intreated hypertensive men. Journal of Human Hyperten-sion 2001; 15:707-713.

130. Dishy V, Sofowora G, Harris PA, et al. The effect of sil-denafil on nitric oxide-mediated vasodilation in healthymen. Clin Pharmacol Ther 2001; 70-270-279.

131. Wilkens H, Guth A, König J, et al. Effect of inhaled ilo-prost plus oral sildenafil in patients with primary pulmo-nary hypertension. Circulation 2001; 104:1218-1222.

132. Schwemmer M, Bassenge E, Stoeter M, et al. Potentia-tion of sildenafil-induced hypotension is minimal withnitrates generating a radical intermediate. Journal ofCardiovascular Pharmacology 2001; 38:149-155.

133. Ichinose, F, Erana-Garcia J, Hromi J, et al. Nebulized sil-denafil is a selective pulmonary vasodilator in lambswith acute pulmonary hypertension. Crit. Care Med.2001 Vol. 29 5:1000-1005.

134. Berkels R, Klotz T, Sticht G, et al. Modulation of humanplatelet aggregation by the phosphodiesterase Type 5inhibitor sildenafil. Journal of Cardiovascular Pharmaco-logy 2001; 37:413-421.

135. Phillips BG, Kato M, Pesek CA, et al. Sympathetic acti-vation by sildenafil. Circulation 2000; 102:3068-3073.

136. Medina P, Segarra G, Martinez-Leon JB, et al. Relaxa-tion induced by cGMP phosphodiesterase inhibitors sil-denafil and zaprinast in human vessels. Ann Thorac Surg2000; 70:1327-1331.

538

137. Medina P, Segarra G, Vila JM, et al. Effects of sildena-fil on human penile blood vessels. Urology 2000;56:539-543.

138. Swissa M, Ohara T, Lee M-H, et al. Sildenafil-nitricoxide donor combination promotes ventricular tachyar-rhythmias in the swine right ventricle. Am J PhysiolHeart Circ Physiol 2002; 282:H1787-1792.

139. Sakuma I, Akaishi Y, Tomioka H, et al. Interactions ofsildenafil with various coronary vasodilators in isolatedporcine coronary artery. European Journal of Pharmaco-logy 2002; 437:155.163.

140. Ishizuka N, Saito K, Akima M, et al. Hypotensive inter-action of sildenafil and nicorndil in rats through thecGMP pathway but not by KATP channel activation. Jpn.

J. Pharmacol 2000; 84:316-324.

141. Piccirrillo G, Nocco M, Lionetti M, et al. Effects of sil-denafil citrate (Viagra) on cardiac repolarizaton and onautonomic control in subjects with chronic heart failure.Am Heart J 2002; 143:703-710.

142. Medina P, Segarra G, Martinez-Leon JB, et al. Relaxa-tion and cGMP formation in response to sildenafil andsodium nitroprusside in saphenous veins from normoten-sive and hypertensive patients. Am J Hypertens 2002;15:798-802.

143. Israilov S, Niv E, Livne PM, et al. Intracavernous injec-tions for erectile dysfunction in patients with cardiovas-cular diseases and failure or contraindications for silde-nafil citrate.International Journal of Impotence Research2002; 14:38-43.

144. Chiu YJ, Reid IA. Effect of Sildenafil on rennin secre-tion in human subjects. Exp Bio Med 2002; 227:620-625.

145. Thèbaud B, Michelakis E, Wu X-C, et al. Sildenafilreverses O2 constriction of the rabbit ductus arteriosusbinhibiting type 5 phosphodiesterase and activatingBKCa Channels. Pediatric Research 2002; 52:19-24.

146. Yoo KY, Kim HS, Moon J-D, et al. .Sildenafil (Via-gra®) augments sodium nitroprusside-induced but notnitroglycerin-induced hypotension in dogs. Anesth Ana-log 2002; 94:1505-1509

147. O’Rourke MF, Nichols WW. Potential for use of pulsewave analysis in determining the interaction between sil-denafil and glyceryl trinitrate. Clin. Cardiol. 2002;25:295-299.

148. Mochida H, Inoue H, Takagi M, et al. Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a dif-ferent vasorelaxant property in the isolated rat aorta.European J. of Pharmacology 2002; 440:45-52.

149. Senzaki H, Smith CJ, Juang GJ, et al. Cardiac phospho-diesterase 5 (cGMP-specific) modulates b-adrenergicsignaling in vivo and is down-regulated in heart failure.FASEB 2001; 15:1718-1726.

150. Stuckey BG. Jadzinsky MN. Murphy LJ. Montorsi F.Kadioglu A. Fraige F. Manzano P. Deerochanawong C.Sildenafil citrate for treatment of erectile dysfunction inmen with type 1 diabetes: results of a randomizedcontrolled trial Diabetes Care. 26(2):279-84, 2003

151. DeBusk RF, Pepine CJ, Glasser DB, Shpilsky A, DeRiesthal H, Sweeney M. Efficacy and safety of sildenafilcitrate in men with erectile dysfunction and stable coro-nary artery disease Am J Cardiol, 2004, 93: 147-153

539

2. PDE5 INHIBITORS: VARDENAFIL

Five (5) level 1 publications [1-4, 12]

• Diabetic ED Patients

One (1) level 1 publication [5].

• Post-prostatectomy

One (1) level 1 publication [6].

Five (5) level 1 publications [7-10, 12].

One (1) level 1 publication [11]

1. Klotz T, Sachse R, Heidrich A, Jockenhovel F, Rohde G,Wensing G, Horstmann R, Engelmann R. Vardenafilincreases penile rigidity and tumescence in erectile dys-function patients: a RigiScan and pharmacokinetic study.World J Urol 2001;19:32-9.

2. Porst H, Rosen R, Padma-Nathan H, Goldstein I, Guilia-no F, Ulbrich E, Bandel T, and the Vardenafil StudyGroup. The efficacy and tolerability of vardenafil, a newselective phosphodiesterase type 5 inhibitor, in patientswith erectile dysfunction: the first at-home clinical trial.Int J Impot Res 2001;13:192-9.

3. Porst H, Young J, Schmidt AC, Buvat J, and the Interna-tional Vardenafil Study Group. Efficacy and tolerabilityof Vardenafil for the treatment of erectile dysfunction inpatient subgroups. Urology 2003;62:519–524.

4. Hellstrom W, Gittelman M, Karlin G, Thibonnier M,Padma-Nathan H. Vardenafil for Treatment of Men WithErectile Dysfunction: Efficacy and Safety in a Randomi-zed, Double-Blind, Placebo-Controlled Trial. J. Androlo-gy 2002;23(6):763-71

5. Goldstein I, Young JM, Fischer J, Bangerter K, SegersonT, Taylor T. Vardenafil, a New Phosphodiesterase Type 5Inhibitor, in the Treatment of Erectile Dysfunction in MenWith Diabetes: A multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003;26:777-83.

6. Brock G, Lipshultz L, Karlin G, Gleave M, Seger M,Padma-Nathan H. Safety and Efficacy of Vardenafil forthe Treatment of Men With Erectile Dysfunction Subse-quent to Radical Retropubic Prostatectomy. J. Urology2003;170:1278-1283.

7. Hellstrom W, Gittelman M, Karlin G, Segerson T, Thi-bonnier M, Taylor T, Padma-Nathan H, on behalf of the

Vardenafil Study Group. Sustained efficacy and tolerabi-lity of vardenafil (Levitra®), a highly potent, selectivephosphodiesterase-5 inhibitor, in men with erectile dys-function: Results of a randomized, double-blind, 26-weekplacebo-controlled pivotal trial. Urology 2003;61 (Suppl4A):8-14.

8. Rajagopalan P, Mazzu A, Xia C, Dawkins R, SundaresanP. Effect of high-fat breakfast and moderate-fat eveningmeal on the pharmacokinetics of vardenafil, an oral phos-phodiesterase-5 inhibitor for the treatment of erectile dys-function. J Clin Pharmacol 2003;43:260-7.

9. Nagao K, Ishii H, Kamidono S, Nagata H. Safety and effi-cacy of vardenafil (Levitra) in patients with erectile dys-function: Results of a bridging study in Japan. Int J Urol2004 (in press).

10. Saenz de Tejada I, Glina S, Becher E, Ulbrich E, and theVardenafil Study group. Vardenafil exhibits long-termefficacy and safety for up to 52 weeks. Int J Impot Res2002;14 (Suppl 4):S22/ S59.

11. Thadani U, Smith W, Nash S, Bittar N, Glasser S,Narayan P, Stein R, Larkin S, Mazzu A, Tota R, Pome-rantz K, Sundaresan P. Effect of vardenafil on the cardio-vascular responses to exercise in men with coronary arte-ry disease. J Am Coll Cardiol 2002;40:2006-2012i

12. Hatzichristou D, Montorsi F, Buvat J, Laferriere N, Ban-del T, Porst H, for the Vardenafil Study Group. The effi-cacy and safety of flexible-dose vardenafil (Levitra) in abroad population of European men. Eur. Urol 2004; inpress

VARDENAFIL REFERENCES

d) Cardiovascular Investigations

c) General and Class Specific Safety Issues

b) Special Population Efficacy

a) General Efficacy

540

541

Det

aile

d re

view

of

impo

rtan

t Var

dana

fil c

linic

al p

ublic

atio

ns

542

Det

aile

d re

view

of

impo

rtan

t Var

dana

fil c

linic

al p

ublic

atio

ns

543

Det

aile

d re

view

of

impo

rtan

t Var

dana

fil c

linic

al p

ublic

atio

ns

•V

fS -

Val

id f

or s

afet

y•

ITT

- In

tent

-to-

Tre

at P

opu-

latio

n•

VfE

- V

alid

for

Eff

icac

y•

VPP

- V

alid

per

pro

toco

l

•M

C -

Mul

ticen

ter

•R

= R

ando

miz

ed•

DB

= D

oubl

e B

lind

•Pl

A=

Pla

cebo

•II

EF-

EF

Dom

ain

(LO

CF)

•In

terc

ours

e su

cces

s•

GA

Q -

Glo

bal A

sses

smen

tqu

estio

n•

SEP-

2 (L

OC

F) -

Dia

ry(S

exua

l Enc

ount

er P

rofi

le)

Que

stio

n 2

- (L

ast O

bser

va-

tion

Car

ried

For

war

d•

SEP-

3 (L

OC

F) -

Dia

ry(S

exua

l Enc

ount

er P

rofi

le)

Que

stio

n 3

- (L

ast O

bser

va-

tion

Car

ried

For

war

d

3. PDE5 INHIBITORS: TADALAFIL

Three (3) level 1 publications [1-3]

• Diabetic ED Patients

One (1) level 1 publication [4].

Four (4) level 1 publications, including a spermassessment study [1-5].

One (1) level 2 publication (open label) [6]

One (1) level 1 publication [7].

1. Brock GB, McMahon CG, Chen KK, Costigan T, Shen W,Watkins V, Anglin G, Whitaker S.Efficacy and safety oftadalafil for the treatment of erectile dysfunction:results ofintegrated analyses. J Urol. 2002 Oct;168(4 Pt 1):1332-6.

2. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varane-se L, Rosen R Efficacy of tadalafil for the treatment oferectile dysfunction at 24 and 36 hours after dosing: a ran-domized controlled trial. Urology. 2003 Jul;62(1):121-5

3. Padma-Nathan H, McMurray JG, Pullman WE, WhitakerJS, Saoud JB, Ferguson KM,Rosen RC; IC351 On-Demand Dosing Study Group. On-demand IC351 (Cialis)enhances erectile function in patients with erectile dys-function. Int J Impot Res. 2001 Feb;13(1):2-9.

4. Saenz de Tejada I, Anglin G, Knight JR, Emmick JT.Effects of tadalafil on erectile dysfunction in men with dia-betes. Diabetes Care. 2002 Dec;25(12):2159-64.

5. Hellstrom WJ, Overstreet JW, Yu A, Saikali K, Shen W,Beasley CM Jr, Watkins VS Tadalafil has no detrimentaleffect on human spermatogenesis or reproductive hor-mones. J. Urol. 2003 Sept; 170(3) : 887-91

6. Montorsi F., Verheyden B., Meuleman E., Jünemann K-P,Moncada I., Valiquette L., Casabé A., Pacheco C., DenneJ., Knight J., Segal S., Watkins V.S. Long-term safety tolerability of tadalafil in the treatment of erectile dys-function. Eur. Urol 2004, 45: 339-345

7. Kloner RA, Hutter AM, Emmick JT, Mitchell MI, DenneJ, Jackson G. Time course of the interaction between tada-lafil and nitrates. J Am Coll Cardiol. 2003 Nov19;42(10):1855-60.

REFERENCES TADALAFIL

d) Cardiovascular Investigations

c) General and Class Specific Safety Issues

b) Special Population Efficacy

a) General Efficacy

544

545

Det

aile

d re

view

of

impo

rtan

t Tad

alaf

il c

linic

al p

ublic

atio

ns (

To b

e co

mpl

eted

)

546

Det

aile

d re

view

of

impo

rtan

t Tad

alaf

il c

linic

al p

ublic

atio

ns (

To b

e co

mpl

eted

)

• II

EF

= I

nter

natio

nal I

ndex

of

Ere

ctile

Fun

ctio

n•

EF

= E

rect

ile F

unct

ion

• >

Int

erco

urse

suc

ess

= S

EP

3SE

P3 =

sex

ual e

ncou

nter

pro

file

que

stio

n 3

(whi

ch is

a s

elf

- re

port

of

inte

rcou

rse

succ

ess)

• G

AQ

= G

loba

l Ass

essm

ent Q

uest

ion

- “d

id th

is d

rug

or tr

eatm

ent i

mpo

ve y

our

erec

tion

?

4. ALPHA-BLOCKERS: PHENTOLAMINE

Four (4) level 2 [1-4] and one (1) level 3 publication [5]

Absence of a specific publication in this category

Four (4) level 2 [1-4] and one (1) level 3 publication [5]

Absence of a specific publication in this category

1. Ugarte F and Hurtado-Coll A: Comparison of the efficacyand safety of sildenafil citrate (Viagra) and oral phentola-mine for the treatment of erectile dysfunction. Int J ImpotRes. 14 Suppl 2: S48-53, 2002.

2. Lammers PI, Rubio-Aurioles E, Castell R, Castaneda J,Ponce de Leon R, Hurley D, Lipezker M, Loehr LA and-Lowrey F: Combination therapy for erectile dysfunction: arandomized, double blind, unblinded active-controlled,cross-over study of the pharmacodynamics and safety ofcombined oral formulations of apomorphine hydrochlori-de, phentolamine mesylate and papaverine hydrochloridein men with moderate to severe erectile dysfunction. Int JImpot Res. 14: 54-9; discussion 60., 2002.

3. Hatzichristou DG, Apostolidis A, Tzortzis V, Hatzimoura-tidis K and Kouvelas D: Effects of oral phentolamine,taken before sleep, on nocturnal erectile activity: a doubleblind, placebo-controlled, crossover study. Int J ImpotRes. 13: 303-8., 2001.

4 Becker AJ. Stief CG. Machtens S. Schultheiss . HartmannU. Truss MC. Jonas U. Oral phentolamine as treatrnent forerecti le dysfunction . Journal of Urology. 159(4):1214-6,1998 Apr.

5. Padma-Nathan H, Goldstein I, Klimberg I, Coogan C,Auerbach S andLammers P: Long-term safety and effica-cy of oral phentolamine mesylate (Vasomax) in men with-mild to moderate erectile dysfunction. Int J Impot Res. 14:266-70., 2002.

5. ALPHA-BLOCKERS: YOHIMBINE

Four (4) level 2 (one demonstrating efficacy [1] and three demonstrating non-efficacy) [2-4], andone (1) level 3 publication [5]

Absence of a specific publication in this category

Four (4) level 2 [1-4], and one (1) level 3 publication [5]

Absence of a ED specific publication in this category

1. Ernst E and Pittler MH: Yohimbine for erectile dysfunc-tion: a systematic review and meta- analysis of randomi-zed clinical trials. J Urol. 159(2): 433-6., 1998.

2. Teloken C, Rhoden ELL, Sogari P, Dambros M and SoutoCA: Therapeutic effects of high dose yohimbine hydro-chloride on organic erectile dysfunction. J Urol.159(1):122-4., 1998.

3 . Vogt HJ, Brandl P, Kockott G, Schmitz JR, Wiegand MH,Schadrack J and Gierend M: Double-blind, placebo-controlled safety and efficacy trial with yohimbine hydro-chloride in the treatment of nonorganic erectile dysfunc-tion. Int J ImpotRes. 9(3): 155-61., 1997.

4. Kunelius P, Hakkinen J andLukkarinen O: Is high-doseyohimbine hydrochloride effective in the treatment ofmixed-type impotence? A prospective, randomized-controlled double- blind crossover study. Urology. 49(3):441-4., 1997.

5. Guay AT, Spark RF, Jacobson J, Murray FT and GeisserME: Yohimbine treatment of organic erectile dysfunctionin a dose- escalation trial. Int J Impot Res. 14(1):25-31.,2002.

YOHIMBINE REFERENCES

d) Cardiovascular Investigations

c) General and Class Specific Safety Issues

b) Special Population Efficacy

a) General Efficacy

REFERENCESPHENTOLAMINE

d) Cardiovascular Investigations

c) General and Class Specific Safety Issues

b) Special Population Efficacy

a) General Efficacy

547

6. OTHER ALPHA-BLOCKER COMBINATIONS

• Yohimbine and L-Arginine

One (1) level 2 publication [1] and phase 2 development status

• L-Arginine

One (1) level two publication. Non-effective [2]

• Trazodone

Three (3) level 2 publications [3-6] demonstrating non-efficacy and one (1) level 2publication that was over 5 years old demonstra-ting some efficacy [7].

• Trazodone and Yohimbine

One (1) level 2 publication [8].

1. Lebret T, Herve JM, Gorny P, Worcel M and Botto H: Effi-cacy and safety of a novel combination of L-arginine glu-tamate and yohimbine hydrochloride: a new oral therapyfor erectile dysfunction. Eur Urol. 41(6): 608-13;2002.

2. Klotz T. Mathers MJ. Braun M. Bloch W. Engelmann U.Effectiveness of oral L- arginine in first-line treatment oferectile dysfunction in a contolled crossover study. Urolo-gia Internationalis. 63(4):220-3, 1999.

3. Enzlin P, Vanderschueren D, Bonte L, Vanderborght W,Decleroq G and Demyttenaere K: Trazodone: a double-blind, placebo-controlled, randomized study of its effectsin patients with erectile dysfunction without major organicfindings. Int J Impot Res. 12(4). 223-8., 2000

4. Costabile RA andSpevak M: Oral trazodone is not effecti-ve therapy for erectile 7 dysfunction: a double-blind, pla-cebo controlled trial. J Urol. 161(6): 1819-22., 1999.

5. Meinhardt W, Schmitz PI, Kropman RF, de la Fuente RB,Lycklama a Nijeholt A.A and Zwartendijk J: Trazodone, adouble blind trial for treatment of erectile dysfunction. IntJ Impot Res. 9(3): 163-5., 1997. Level 2: not effective

6. Aydin S. Odabas O. Ercan M. Kara H. Agargun MY.Effi-cacy of testosterone, trazodone and hypnotic suggestion inthe treatment of non-organic male sexual dysfunction. Bri-tish Journal of Urology. 77(2):256-60, 1996 Feb.

7. Kurt U, Ozkardes H, Altug U, Germiyanoglu C, Gurdal MandErol D: The efficacy of anti-serotoninergic agents inthe treatment of erectile dysfunction. J Urol. 152: 407-9.,1994.

8. Montorsi F, Strambi LF, Guazzoni G, Galli L, Barbieri L,Rigatti P, Pizzini G andMiani A: Effect of yohimbine-tra-zodone on psychogenic impotence: a randomized, double-blind, placebo-controlled study. Urology. 44: 732-6., 1994.

7. DOPAMINE AGONIST: APOMORPHINE SL

Two (2) level 1 [1,2],two (2) level 2 [3,4] and

one (1) level 3 publication [5]

Two (2) level 2 studies not specifically designed forthe subgroups [1,2]

Two (2) level 1 [1,2], two (2) level 2 [3,4] and one (1) level 3 publication [5].

Two (2) level 2 publications [1,2]not specifically designed to adress the issue

1. Von Keitz AT, Stroberg P, Bukofzer S, Mallard N, HibberdM.: A European multicentre study to evaluate the tolerabi-lity of apomorphine sublingual administered in a forceddose-escalation regimen in patients with erectile dysfunc-tion. BJU Int. 2002 Mar;89(4):409-15

2. Dula E, Keating W, Siami PF, Edmonds A, O’neil J, Butt-ler S.: Efficacy and safety of fixed-dose and dose-optimi-zation regimens of sublingual apomorphine versus place-bo in men with erectile dysfunction. The ApomorphineStudy Group. Urology. 2000 Jul;56(1):130-5

3. Dula E, Bukofzer S, Perdok R, George M.: Double-blind,crossover comparison of 3 mg apomorphine SL with pla-cebo and with 4 mg apomorphine SL in male erectile dys-function. Eur Urol. 2001 May;39(5):558-3

4. Mulhall JP, Bukofzer S, Edmonds AL, George M.: Anopen-label, uncontrolled dose-optimization study of sub-lingual apomorphine in erectile dysfunction. Clin Ther.2001 Aug;23(8):1260-71

5. Heaton JP, Dean J, Sleep DJ.: Sequential administrationenhances the effect of apomorphine SL in men with erec-tile dysfunction. Int J Impot Res. 2002 Feb;14(1):61-4

APOMORPHINE SLREFERENCES

d) Cardiovascular Investigations

c) General and Class Specific Safety Issues

b) Special Population Efficacy

a) General Efficacy

OTHER ALPHA-BLOCKER REFERENCES

548

549

Det

aile

d re

view

of

impo

rtan

t Apo

rmor

phin

e SL

publ

icat

ions

8. OTHER CENTRALLY ACTING AGENTS

• Melanocortin Agonists/ MTII

Three (3) level 2 publications. Phase II development [1-3]

• Delequamine

Three (3) level 2 publications [4-6].

• Naltrexone

Two (2) level 2 publications [7-8]

• Nalmefene

One (1) level 3 publication [9]

Melanocortin Agonists / MTH

1. Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ,Dorr R and Levine N: Synthetic melanotropic peptide ini-tiates erections in men with psychogenic erectile dysfunc-tion: double-blind, placebo controlled crossover study. JUrol. 160: 389-93., 1998.

2. Wessels H, Gralnek D, Dorr R, Hruby VJ, Hadley ME andLevine N: Effect of an alpha-melanocyte stimulating hor-mone analog on penile erection and sexual desire in menwith organic erectile dysfunction. Urology. 56: 641-6.,2000.

3. Wessells H, Levine N, Hadley ME, Dorr R and Hruby V:Melanocortin receptor agonists, penile erection, andsexual motivation: human studies with Melanotan II. Int JImpot Res. 12 Suppl 4: S74-9., 2000.

Delequamine

1. Bancroft J, Munoz M, Beard M and Shapiro C: The effectsof a new alpha-2 adrenoceptor antagonist on sleep andnocturnal penile tumescence in normal male volunteersand men with erectile dysfunction. Psychosom Med. 57:345-56., 1995.

2. Munoz M, Bancroft J and Turner M: Evaluating the effectsof an alpha-2 adrenoceptor antagonist on erectile functionin the human male. 1. The erectile response to erotic sti-muli in volunteers. Psychopharmacology (Berl). 115: 463-70., 1994.

3. Munoz M, Bancroft J and Beard M: Evaluating the effectsof an alpha-2 adrenoceptor antagonist on erectile functionin the human male. 2. The erectile response to erotic sti-muli in men with erectile dysfunction, in relation to ageand in comparison with normal volunteers. Psychophar-macology (Berl). 115: 471-7., 1994.

Nalmefene

1. Billington CJ, Shafer RB and Morley JE: Effects of opioidblockade with nalmefene in older important men. Life Sci.47: 799-805, 1990.

Naltrexone

1. Brennemann W, Stitz B, Van Ahlen H, Brensing KA andKlingmuller D: Treatment of idiopathic erectile dysfunc-tion in men with the opiate antagonist naltrexone - adouble-blind study. J Androl. 14:407-10., 1993.

2. van Ahlen H, Piechota HJ, Kias HJ, Brennemann W andKlingmuller D: Opiate antagonists in erectile dysfunction:a possible new treatment option? Results of a pilot studywith naltrexone. Eur Urol. 28: 246-50, 1995.

CENTRALLY ACTING AGENTSREFERENCES

550

1. INTRACAVERNOSAL INJECTION THERAPY

• Alprostadil (PGE1)

Four (4) level 1 [1-4],eight (8) level 2, [5-12] and eight (8) level 3 publications [13-20]

One (1) Level 1 [1],two (2) level 2 [11, 21] and one (1) level 3 publication [22]

Four (4) level 1 [1-4], eight (8) level 2 [23-30], and eight (8) level 3 publication [31-33, 16-20]

One (1) level 2 publication [34]

• Papaverine HCl and Combination Therapy

There are three (3) level 2 [21, 35-36] and one (1) level 3 publication [37].

General lack of regulatory approval despite a largeclinical experience

1. Heaton JP, Lording D, Liu SN, Litonjua AD, Guangwei L,Kim SC, Kim JJ, Zhi-Zhou S, Israr D, Niazi D, Rajatana-vin R, Suyono S, Benard F, Casey R, Brock G, BelangerA. Intracavernosal alprostadil is effective for the treat-ment of erectile dysfunction in diabetic men Int J ImpotRes. 2001 Dec;13(6):317-21

2. Porst H, Buvat J, Meuleman E, Michal V, Wagner G.Intracavernous Alprostadil Alfadex--an effective and welltolerated treatment for erectile dysfunction. Results of along-term European study. Int J Impot Res. 1998 Dec;10(4) : 225-31

3. Linet OI, Ogrinc FG Efficacy and safety of intracaverno-sal alprostadil in men with erectile dysfunction. TheAlprostadil Study Group. N Engl J Med. 1996 Apr4;334(14):873-7

4. Choi HK, Adimoelja A, Kim SC, Soebadi DM, SeongDH, Garceau RJ. A dose-response study of alprostadil ste-rile powder (S.Po.) (Caverject) for the treatment of erec-tile dysfunction in Korean and Indonesian men. Int JImpot Res. 1997 Mar;9(1):47-51

5. Porst H. The rationale for prostaglandin E1 in erectile fai-lure: a survey of worldwide experience. J Urol. 1996Mar;155(3):802-15

6. Hauck EW, Altinkilic BM, Schroeder-Printzen I, RudnickJ, Weidner W Prostaglandin E1 long-term self-injectionprogramme for treatment of erectile dysfunction--a fol-low-up of at least 5 years. Andrologia. 1999;31 Suppl1:99-103

7. Kunelius P, Lukkarinen O Intracavernous self-injection ofprostaglandin E1 in the treatment of erectile dysfunction.Int J Impot Res. 1999 Feb;11(1):21-4

8. Tsai YS, Lin JS, Lin YM. Safety and efficacy of alprosta-dil sterile powder (S. Po., CAVERJECT) in diabeticpatients with erectile dysfunction. Eur Urol. 2000Aug;38(2):177-83

9. Montorsi F, Guazzoni G, Barbieri L, Ferini-Strambi L,Iannaccone S, Calori G, Nava L, Rigatti P, Pizzini G,Miani A. Genital plus audiovisual sexual stimulation fol-lowing intracavernous vasoactive injection versus re-dosing for erectile dysfunction--results of a prospectivestudy. J Urol. 1998 Jan;159(1):113-5

10. Shabsigh R, Padma-Nathan H, Gittleman M, McMurrayJ, Kaufman J, Goldstein I Intracavernous alprostadil alfa-dex (EDEX/VIRIDAL) is effective and safe in patientswith erectile dysfunction after failing sildenafil (Viagra).Urology. 2000 Apr;55(4):477-80

11. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, NavaL, Barbieri L, Rigatti P, Pizzini G, Miani A . Recovery ofspontaneous erectile function after nerve-sparing radicalretropubic prostatectomy with and without early intraca-vernous injections of alprostadil: results of a prospective,randomized trial. J Urol. 1997 Oct;158(4):1408-10

12. Elhanbly S, Schoor R, Elmogy M, Ross L, Hegazy A,Niederberger C. What nonresponse to intracavernousinjection really indicates: a determination by quantitativeanalysis. J Urol. 2002 Jan;167(1):192-6.

13. Abdallah HM . Comparison of Alprostadil (Caverject)and a combination of vasoactive drugs as local injectionsfor the treatment of erectile dysfunction. Int UrolNephrol. 1998;30(5):617-20.

14. Valdevenito R, Melman A. Intracavernous self-injectionpharmacotherapy program: analysis of results and com-plications. Int J Impot Res. 1994 Jun;6(2):81-91

15. Ghanem H, Sherif T, Adbel-Gawad T, Asaad T. Short termuse of intracavernous vasoactive drugs in the treatment ofpersistent psychogenic erectile dysfunction. Int J ImpotRes. 1998 Dec;10(4):211-4.

16. Ismail M, Abbott L, Hirsch IH. Experience with intraca-vernous PGE-1 in the treatment of erectile dysfunction:dose considerations and efficacy. : Int J Impot Res. 1997Mar;9(1):39-42

17. Lundberg L, Olsson JO, Kihl B. Long-term experience ofself-injection therapy with prostaglandin E1 for erectiledysfunction. Scand J Urol Nephrol. 1996 Oct;30(5):395-7

18. Purvis K, Brekke I, Christiansen E. Determinants of satis-factory rigidity after intracavernosal injection with pros-taglandin E1 in men with erectile failure. Int J Impot Res.1996 Mar;8(1):9-16.

ALPROSTADIL REFERENCES

d) Cardiovascular Investigations

c) General and Class Specific Safety Issues

b) Special Population Efficacy

a) General Efficacy

III. LOCAL ED THERAPIES

551

19. Colli E, Calabro A, Gentile V, Mirone V, Soli M. Alpros-tadil sterile powder formulation for intracavernous treat-ment of erectile dysfunction. Eur Urol. 1996;29(1):59-62

20. Canale D, Giorgi PM, Lencioni R, Morelli G, Gasperi M,Macchia E Long-term intracavernous self-injection withprostaglandin E1 for the treatment of erectile dysfunction.Int J Androl. 1996 Feb;19(1):28-32.

21. Montorsi F, Guazzoni G, Bergamaschi F, Zucconi M,Rigatti P, Pizzini G, Miani A, Pozza G Clinical reliabili-ty of multi-drug intracavernous vasoactive pharmacothe-rapy for diabetic impotence. Acta Diabetol. 1994Apr;31(1):1-5

22. Zaslau S, Nicolis C, Galea G, Britanico J, Vapnek JM.Asimplified pharmacologic erection program for patientswith spinal cord injury. J Spinal Cord Med. 1999 Win-ter;22(4):303-7

23. Godschalk M, Gheorghiu D, Katz PG, Mulligan T. Alka-lization does not alleviate penile pain induced by intraca-vernous injection of prostaglandin E1. J Urol. 1996Sep;156(3):999-1000.

24. Lehmann K, Casella R, Blochlinger A, Gasser TC . Rea-sons for discontinuing intracavernous injection therapywith prostaglandin E1 (alprostadil). Urology. 1999Feb;53(2):397-400.

25. Chew KK, Stuckey BG, Earle CM, Dhaliwal SS, KeoghEJ.Penile fibrosis in intracavernosal prostaglandin E1injection therapy for erectile dysfunction. : Int J ImpotRes. 1997 Dec;9(4):225-9

26. Hirsch IH, Smith RL, Chancellor MB, Bagley DH, Car-sello J, Staas WE Jr.Use of intracavernous injection ofprostaglandin E1 for neuropathic erectile dysfunction.Paraplegia. 1994 Oct;32(10):661-4.

27. Von Heyden B, Donatucci CF, Kaula N, Lue TF Intraca-vernous pharmacotherapy for impotence: selection ofappropriate agent and dose. J Urol. 1993 May;149(5 Pt2):1288-90

28. Israilov S, Niv E, Livne PM, Shmueli J, Engelstein D,Segenreich E, Baniel J Intracavernous injections for erec-tile dysfunction in patients with cardiovascular diseasesand failure or contraindications for sildenafil citrate. Int JImpot Res. 2002 Feb;14(1):38-43

29. Richter S, Vardi Y, Ringel A, Shalev M, Nissenkorn I.Intracavernous injections: still the gold standard for treat-ment of erectile dysfunction in elderly men.Int J ImpotRes. 2001 Jun;13(3):172-5

30. Ribe N, Rajmil O, Bassas L, Jurado C, Pomerol JM. Res-ponse to intracavernous administration of 3 differentdrugs in the same group of patients with erectile dysfunc-tion. Arch Esp Urol. 2001 May;54(4):355-9 Level 3

31. Abdallah HM . Comparison of Alprostadil (Caverject)and a combination of vasoactive drugs as local injectionsfor the treatment of erectile dysfunction. Int UrolNephrol. 1998;30(5):617-20.

32. Valdevenito R, Melman A. Intracavernous self-injectionpharmacotherapy program: analysis of results and com-plications. Int J Impot Res. 1994 Jun;6(2):81-91

33. Ghanem H, Sherif T, Adbel-Gawad T, Asaad T. Short termuse of intracavernous vasoactive drugs in the treatment ofpersistent psychogenic erectile dysfunction. Int J ImpotRes. 1998 Dec;10(4):211-4.

34. Livi U, Faggian G, Sorbara C, Gambino A, Calabro A,Artibani W, Bortolotti U, Pagano F. Use of prostaglandinE1 in the treatment of sexual impotence after heart trans-plantation: initial clinical experience. J Heart Lung Trans-plant. 1993 May-Jun;12(3):484-6

35. Shenfeld O, Hanani J, Shalhav A, Vardi Y, Goldwasser B.Papaverine-phentolamine and prostaglandin E1 versuspapaverine-phentolamine alone for intracorporeal injec-tion therapy: a clinical double-blind study. J Urol. 1995Sep;154(3):1017-9

36. Meinhardt W, Lycklama a Nijeholt AA, Kropman RF, Ver-meij P, Zwartendijk J. Comparison of a mixture of papa-verine, phentolamine and prostaglandin E1 with otherintracavernous injections. Eur Urol. 1994;26(4):319-21

37. Bechara A, Casabe A, Cheliz G, Romano S, FredotovichN. Prostaglandin E1versus mixture of prostaglandin E1,papaverine and phentolamine innonresponders to highpapaverine plus phentolamine doses. J Urol. 1996Mar;155(3):913-4

552

2. INTRAURETHRAL THERAPY

• Alprostadil (PGE1)

Three (3) level 1 [1-3] and

two (2) level 2 publications [4, 9]

one (1) level 1 [19] andone (1) level 3 [6] publication

Three (3) level 1 [1-3],one (1) level 2 [4], and nine (9) level 3 [6-8, 10-15] publications

Absence of a specific publication in this category

1. Padma-Nathan H, Hellstrom WJ, Kaiser FE, Labasky RF,Lue TF, Nolten WE, Norwood PC, Peterson CA, Shab-sigh R, Tam PY. Treatment of men with erectile dysfunc-tion with transurethral alprostadil. Medicated UrethralSystem for Erection (MUSE) Study Group. N Engl JMed. 1997 Jan 2;336(1):1-7.

2. Williams G, Abbou CC, Amar ET, Desvaux P, Flam TA,Lycklama a Nijeholt GA, Lynch SF, Morgan RJ, MullerSC, Porst H, Pryor JP, Ryan P, Witzsch UK, Hall MM,Place VA, Spivack AP, Gesundheit N. Efficacy and safe-ty of transurethral alprostadil therapy in men with erecti-le dysfunction. MUSE Study Group. Br J Urol. 1998Jun;81(6):889-94.

3. Shabsigh R, Padma-Nathan H, Gittleman M, McMurrayJ, Kaufman J, Goldstein I. Intracavernous alprostadil alfa-dex is more efficacious, better tolerated, and preferredover intraurethral alprostadil plus optional actis: a compa-rative, randomized, crossover, multicenter study. Urology.2000 Jan;55(1):109-13.

4. Williams G, Abbou CC, Amar ET, Desvaux P, Flam TA,Lycklama a Nijeholt GA, Lynch SF, Morgan RJ, MullerSC, Porst H, Pryor JP, Ryan P, Witzsch UK, Hall MM,Place VA, Spivack AP, Todd LK, Gesundheit N. Theeffect of transurethral alprostadil on the quality of life ofmen with erectile dysfunction, and their partners. MUSEStudy Group. Br J Urol. 1998 Dec;82(6):847-54.

5. Costabile RA, Spevak M, Fishman IJ, Govier FE, Hell-strom WJ, Shabsigh R, Nemo KJ, Rapport JL, Tam PY,Weldon KL, Gesundheit N. Efficacy and safety of trans-urethral alprostadil in patients with erectile dysfunctionfollowing radical prostatectomy. J Urol. 1998Oct;160(4):1325-8.

6. Bodner DR, Haas CA, Krueger B, Seftel AD. Intraure-thral alprostadil for treatment of erectile dysfunction inpatients with spinal cord injury. Urology. 1999Jan;53(1):199-202.

7. Werthman P, Rajfer J. MUSE therapy: preliminary clini-cal observations. Urology. 1997 Nov;50(5):809-11.

8. Porst H. Transurethral alprostadil with MUSE (medicatedurethral system for erection) vs intracavernous alprosta-dil--a comparative study in 103 patients with erectile dys-function. Int J Impot Res. 1997 Dec;9(4):187-92.

9. Shokeir AA, Alserafi MA, Mutabagani H. Intracaverno-sal versus intraurethral alprostadil: a prospective rando-mized study. BJU Int. 1999 May;83(7):812-5.

10. Guay AT, Perez JB, Velasquez E, Newton RA, JacobsonJP. Clinical experience with intraurethral alprostadil(MUSE) in the treatment of men with erectile dysfunc-tion. A retrospective study. Medicated urethral system forerection. Eur Urol. 2000 Dec;38(6):671-6.

11. Fulgham PF, Cochran JS, Denman JL, Feagins BA, GrossMB, Kadesky KT, Kadesky MC, Clark AR, RoehrbornCG. Disappointing initial results with transurethralalprostadil for erectile dysfunction in a urology practicesetting. J Urol. 1998 Dec;160(6 Pt 1):2041-6.

12. Pangkahila WI. Evaluation of transurethral application ofalprostadil for erectile dysfunction in Indonesians. AsianJ Androl. 2000 Sep;2(3):233-6.

13. Mulhall JP, Jahoda AE, Ahmed A, Parker M. Analysis ofthe consistency of intraurethral prostaglandin E(1)(MUSE) during at-home use. Urology. 2001Aug;58(2):262-6.

14. Kim SC, Ahn TY, Choi HK, Choi NG, Chung TG, ChungWS, Hwang TK, Hyun JS, Jung GW, Kim CI, Kim JJ,Kim SW, Lee CH, Lee KS, Lee WH, Min KS, Moon KH,Paic JS, Park KS, Park NC, Park YK, Seo JK, Seo KK,Shin JS, Yoon YR, Lee WC. Multicenter study of thetreatment of erectile dysfunction with transurethralalprostadil (MUSE) in Korea. Int J Impot Res. 2000Apr;12(2):97-101.

15. Khan MA, Raistrick M, Mikhailidis DP, Morgan RJ.MUSE: clinical experience. Curr Med Res Opin.2002;18(2):64-7.

INTRAURETHRAL THERAPYREFERENCES

d) Cardiovascular Investigations

c) General and Class Specific Safety Issues

b) Special Population Efficacy

a) General Efficacy

553

3. TOPICAL THERAPIES

• Alprostadil combined with a proprietary Per-meation Enhancer

There are no Level I publications. There are two (2) Level 2 [1, 2].In addition 2 (1) level 2 publication exists for ano-ther combination that are in Phase II development[3,4] as well as one (1) level 2 publication [5] fortopical PGE1 gel alone. In addition there is one (2) Level 3 publication for adifferent formulation of PGE [6] as well as one (1)Level 3 publication [7] using a combination ofPGE1 and papaverine.

• Papaverine

There is one (1) level 2 publication [8]. Experimental

• Minoxidil

There are three (3) level 2 publications [9-11].Experimental

• Nitroglycerine

There is one (1) level 2 [12] and two (2) level 3publications [13, 14]. Experimental

1. Padma-Nathan H, Steidle C, Salem S Tayse N, Yeager J,Harning R. The efficacy and safety of a topical alprostadilcream, Alprox-TD, for the treatment of erectile dysfunc-tion: two phase 2 studies in mild-to-moderate and severeED. Int J Impot Res. 2003 Feb;15(1):10-7.

2. Steidle, Padma-Nathan et al. Topical alprostadil cream forthe treatment of ED: a combined analysis of the phase IIprogram Urology 60:1077-1082, 2002] publications forone formulation which have completed Phase III studies.

3. McVary KT, Polepalle S, Riggi S, Pelham RW. Topicalprostaglandin E1 SEPA gel for the treatment of erectiledysfunction. J Urol. 1999 Sep;162 (3 Pt 1):726-30.

4. Goldstein, Payton and Schechter . Double blind, Placebocontrolled efficacy and safety study of 1-% alprostadil(Topiglan). Urology 57: 301-305, 2001.

5. Kim ED, McVary KT: Topical Prostaglandin-E1 for theTreatment of Erectile Dysfunction, J Urol 153(6):1828-1830, June 1995.

6. Foldvari, Oguejiofor et al. Liposomal encapusaled PGE inED. Urology 52:838-843, 1998.

7. Chiang Kao Sheu Papaverine and PGE1 Gel applicationsfor impotence. Ann Acad Med Singapore 1995: 24: 767-769.

8. Kim ED, el-Rashidy R, McVary KT: Papaverine topicalgel for treatment of erectile dysfunction. J Urol, 153:361-365; 1995

9. Cavallini, G.: Minoxidil versus nitroglycerin: a prospecti-ve double-blind controlled trial in transcutaneous erectionfacilitation for organic impotence. J. Urol., 146: 50, 1991.

10. Radomski SB, Herschorn S, Rangaswamy S TopicalMinoxidil in the treatment of male erectile dysfunction . JUrol. 1994 May;151(5):1225-6

11. Chancellor MB, Rivas DA, Panzer DE, Freedman MK,Staas WE Jr. Prospective comparison of topical minoxidilto vacuum constriction device and intracorporeal papave-rine injection in treatment of erectile dysfunction due tospinal cord injury. Urology. 1994 Mar;43(3):365-9

12. Owen, J.A., Saunders, F., Harris, C., Fenemore, J., Reid,K., Surridge, D., Condra, M. and Morales, A.: Topicalnitroglycerin: a potential treatment for impotence. J.Urol., 141: 546, 1989.

13. Nunez BD, Anderson DC Jr: Nitroglycerin ointment in thetreatment of impotence. J Urol, 150:1241-1243; 1993.

14. Gramkow J, Lendorf A, Zhu J, Meyhoff HH. Transcuta-neous nitroglycerine in the treatment of erectile dysfunc-tion: a placebo controlled clinical trial. Int J Impot Res.1999 Feb;11(1):35-9.

TOPICAL THERAPIES REFERENCES

554

Grouped following level of Evidence, year of publi-cation and alphabetical order of first author

Clinical safety of oral sildenafil citrate (VIA-GRA) in the treatment of erectile dysfunction. Morales A, Gingell C, Collins M, et al. Internatio-nal J. of Impotence Research 1998; 10:69-74.

Note: Reports safety from a series of double blindand open label studies of large # of patients (4274).No difference in incidence of serious CV adverseevents (including myocardial infarction) betweenplacebo or sildenafil.

Level of Evidence :High level.

◆◆◆

Sildenafil for treatment of erectile dysfunction inmen with diabetes. A randomized controlled trial. Rendell MS, Rajfer J, Wicker PA, et al. JAMA1999; 281:421-426.

Note: Primarily an efficacy study - but it is rando-mized, double blind, placebo-controlled. They dopresent CV adverse events. 3% in sildenfail and 5%in placebo group had cardiovascular events.

Level of Evidence : High level.

◆◆◆

Effect of sildenafil on coronary active and reactivehyperemia. Chen Y, Du R, Traverse JH, et al. Am J PhysiolHeart Circ Physiol 2000; 279:H2319-2325. Note: Study done in chronically instrumented dogs.Sildenafil ↓ mean aortic pressure, no change in HR,LV systolic pressure or LV maximal first time deriva-tive of LV pressure (a measure of LV contractility).Sildenafil ↑ rest and exercise myocardial blood flow.Level of Evidence : High Level.

◆◆◆

Hemodynamic effects of sildenafil in men withsevere coronary artery disease. Hermann HC, Chang G, Klugherz BD, et al. NEngl J. Med 2000; 342:1622-1626.

Note: Oral sildenafil given to men with CAD at timeof catheterization. Small ↓ in systemic and pulmo-nary artery pressure. No effect on pulmonary capil-lary wedge pressure, right atrial pressure, heart rate,cardiac output. No change in coronary diameter orflow. No adverse CV effects. Slight increase incoronary flow reserve.

Level of Evidence : High level.

◆◆◆

Acute type 5 phosphodiesterase inhibition with sil-denafil enhances flow-mediated vasodilation inpatients with chronic heart failure. Katz, SD, Balidemaj K, Homma S, et al. J Am CollCardiol 2000; 36:845-851.

Note: Sildenafil increased endothelium - dependentflow mediated vasodilation (assessed by makingtransient arterial occlusions of the brachial artery andmeasuring reactive flow by ultrasound) in heart fai-lure patients.

Level of Evidence : High level.

◆◆◆

Effects of sildenafil citrate (Viagra) combined withnitrate on the heart. Ishikura F, Beppu S, Hamada T, et al. Circulation2000; 102:2516-2521.

Note: Animal study. Sildenafil did not affect syste-mic blood pressure or pulmonary arterial blood pres-sures. Caused vasodilation in normal coronary. Didnot induce ischemia in artery with critical stenosis.With nitrates ↓ systemic BP and coronary blood flow.

Level of Evidence : High level.

◆◆◆

Cyclic nucleotide phosphodiesterase type 5 activitylimits blood flow to hypoperfused myocardiumduring exercise. Traverse JH, Chen YJ, Du R, et al. Circulation2000; 102:2997-3002.

Note: Shows in an animal model that sildenafilimproves coronary artery blood flow in the setting ofa stenosis.

Level of Evidence : High level.

◆◆◆

2000

1998 - 1999

I : High Level Publications

IV. HIGH AND INTERMEDIATELEVEL OF EVIDENCE CARDIO

VASCULAR PUBLICATIONS IN THEFIELD OF ED

PHARMACO-THERAPY(graded by cardiologists on committeee)

555

Sildenafil citrate potentiates the hypotensive effectsof nitric oxide donor drugs in male patients withstable angina. Webb DJ, Muirhead GJ, Wulff M, et al. J Am CollCardiol 2000; 36:25-31.

Note: Men with stable angina on isosorbide mono-nitrate or glyceryl trinitrate given sildenafil or place-bo. Sildenafil substantially potentiated hypotensiveeffect of nitrates.

Level of Evidence : High level.

◆◆◆

Sildenafil is a pulmonary vasodilator in awakelambs with acute pulmonary hypertension. Welmann J, Ullrich R, Hromi J, et al. Anesthesio-logy 2000; 92:1702-1712.

Notes: Animal study. Awake lambs in which acutepulmonary hypertension is chemically induced.Cumulative sildenafil doses resulted in a cumulativedecrease in pulmonary artery pressure, pulmonaryvascular resistance. Only small fall in systemic arte-rial pressure after the highest dose. Sildenafil did notaugment effect of iNO – a finding that differs fromother studies.

Level of Evidence : High level

◆◆◆

Effect of sildenafil citrate on blood pressure andheart rate in men with erectile dysfunction takingconcomitant antihypertensive medication. Zusman RM, Prisant LM, Brown MJ. Journal ofHypertension 2000; 18:1865-1869.

Note: In men taking a variety of antihypertensivemedicines, sildenafil ↓ blood pressure by -3.6/-1.9mmHg versus -0.8/-0.1 mmHg for those on placebo.Conclusions were that short-term effects of oral sil-denafil on BP and HR in men with ED were smalland not clinically significant in those on antihyper-tensives. In men not on antihypertensives, sildenafildecrease in blood pressure was -2.2/-2.0 mmHg.

Level of Evidence : High level.

◆◆◆

Cardiovascular safety of sublingual apomorphinein patients on stable doses of oral antihypertensiveagents and nitrates. Fagan TC, Buttler S, Marbury T, et al. Am J Car-diol 2001; 88:760-766.

Note: > orthostatic decrease in BP when SL apomor-phine given with ∝ blockers and Ca++ blockers (-10

and -6 mmHg vs. placebo). ↓ in BP with long actingnitrates when patients standing.

Level of Evidence : High level.

◆◆◆

Sildenafil modulates hemodynamics and pulmona-ry gas exchange. Kleinsasser A, Loeckinger A, Hoermann C, et al.Am J Respir Crit Care Med 2001; 163: 339-343.

Notes: Anesthetized pigs received control or silde-nafil while hemodynamics were measured. Sildena-fil ↑ intrapulmonary shunt flow with markeddecreases in PaO2, increased cardiac index, pulmo-nary artery pressure at high doses. The issue ofdecreased arterial O2 and increased cardiac indexdiffers from the other studies.

Level of Evidence : High level.◆◆◆

Effect of sildenafil in patients with erectile dys-function taking antihypertensive therapy. Kloner RA, Brown M, Prisant LM, et al. Am JHypertension 2001; 14:70-73.

Note: No ↑in adverse events related to sildenafil inmen on antihypertensive meds (even if on 3 or more)vs. those not on antihypertensive meds. Overall effi-cacy of sildenafil in this group of patients withhypertension ~70%.

Level of Evidence : High level.◆◆◆

Efficacy and safety of sildenafil citrate for the treat-ment of erectile dysfunction in men with cardiovas-cular disease.Ollson AM, Persson C-A. Int J Clin Pract 2001;55(3):171-176.

Note: Important study in that many of these patientshad CV disease at baseline including hypertension,previous MI, chronic ischemic heart disease, angina.Sildenafil was highly effective (71% had improve-ment) and no treatment related adverse CV events.

Level of Evidence : High Level of Evidence.

◆◆◆

Effect of sildenafil citrate upon myocardial ische-mia in patients with chronic stable angina in thera-py with beta-blockers.Patrizi R, Leonardo F, Pelliccia F, et al. Ital HeartJ 2001; 2(11):841-844.

Note: Sildenafil did not worsen ischemia duringexercise test.

Level of Evidence : High level.◆◆◆

2001

556

Sildenafil citrate (Viagra) does not exacerbate myo-cardial ischemia in canine models of coronary arte-ry stenosis. Przyklenk K, Kloner RA. J Am Coll Cardiol 2001;37:286-292.

Note: Experimental animal study. Sildenafil did notexacerbate ischemia in a model of coronary stenosis.It did render platelets refractory to the inhibitingeffects of adenosine receptor stimulation.

Level of Evidence : High level.

◆◆◆

Cardiovascular events in users of sildenafil: resultsfrom first phase of prescription event monitoring inEngland. Shakir SA, Wilton LV, Boshier A, et al. BMJ 2001;322:651-652.

Note: The very important PEM study of over 5000men in United Kingdom. Compared those on silde-nafil vs. general population. Showed no increase infatal MI or ischemic heart disease. As this was not aplacebo controlled study might be intermediate level,but high n value makes this an important study.

Level of Evidence : High level.

◆◆◆

Cardiac electrophysiologic and hemodynamiceffects of sildenafil, a PDE5 inhibitor, in anestheti-zed dogs. Sugiyama A, Satoh Y, Shiina H, et al. Journal ofCardiovascular Pharmacology 2001; 38:940-946.

Note: Anesthetized closed chest dogs. IV sildenafilat various sub → supratherapeutic doses did notaffect monophasic action potential duration or effec-tive refractory period. Sildenafil decreased periphe-ral resistance; some reflex tachycardia at high dose.

Level of Evidence : High level.

◆◆◆

Sildenafil inhibits hypoxia-induced pulmonaryhypertension.

Zhao L, Mason NA, Morrell NW, et al. Circulation2001; 104:424-428.

Note: Randomized, double blind study, placebocontrolled. Sildenafil attenuated hypoxia – inducedpulmonary hypertension in normal volunteers aswell as mice.

Level of Evidence : High level.

◆◆◆

Cardiovascular effects of sildenafil during exercisein men with known or probable coronary arterydisease. Arruda-Olson AM, Mahoney DW, Nehra A, et al.JAMA 2002; 287:719-725.

Notes: Randomized, double blind, placebo control-led study of patients with ED and known or highlysuspected CAD. Symptom limited supine bicycleechocardiogram exercise tests with sildenafil or pla-cebo. Sildenafil had no effect on symptom, exerciseduration, exercise induced ischemic wall motionabnormalities. Exercise BP and heart rates weresimilar. 4 - 5 Mets reached (similar to intercourse).

Level of Evidence : High level.

◆◆◆

Sildenafil effects on exercise, neurohormonal acti-vation, and erectile dysfunction in congestive heartfailure. Bocchi EA, Guimarães G, Mocelin A, et al. Circu-lation 2002; 106:1097-1103.

Notes: Carefully performed double blind, randomi-zed, placebo controlled study showing that sildenafilwas well tolerated and effective in CHF patients(mostly class II); improved exercise capacity, redu-ced BP and HR with exercise, improved peak VO2and exercise times.

Level of Evidence : High level

◆◆◆

Effects of sildenafil on cardiac repolarization. Chiang C-E, Luk H-N, Wang T-M, Ding P Y-A.Cardiovascular Res 2002; 55:290-299.

Notes: In-vitro study of isolated guinea pig papilla-ry muscles and canine Purkinje fibers, whole-cellpatch clamp techniques in guinea pig ventricularmyocytes, in-vivo ECG recordings of guinea pigs.Action potential duration not affected by therapeuticrange of sildenafil. At high concentration sildenafilshortened action potential duration; QTc was notlengthened by sildenafil, in fact it was shortened inguinea pigs.

Level of Evidence : High level.

◆◆◆

Acute and prolonged effects of sildenafil on bra-chial artery flow-mediated dilatation in type 2 dia-betes. Desouza C, Parulkar A, Lumpkin D, et al. DiabetesCare 2002; 25:1336-1339.

2002

557

Notes: Sildenafil acutely and after two weeks of the-rapy improved brachial - artery flow mediated dila-tation and it persisted for at least 24 hours after thelow dose. Suggests it may improve endothelial func-tion in diabetic patient.

Level of Evidence : High level.

◆◆◆

Sildenafil for treatment of lung fibrosis and pulmo-nary hypertension: a randomised controlled trial. Ghofrani HA, Wiedemann R, Rose F, et al. Lancet2002; 360:895-900.

Note:16 patients with pulmonary hypertensionsecondary to pulmonary fibrosis. Sildenafil reducedpulmonary vascular resistance. Sildenafil improvedarterial partial pressure of 02.

Level of Evidence : High level.

◆◆◆

Combination therapy with oral sildenafil and inha-led iloprost for severe pulmonary hypertension.Ghofrani HA, Wiedemann R, Rose F, et al. AnnIntern Med. 2002; 136:515-522.

Notes: Thirty patients with pulmonary hypertensionin an ICU setting received inhaled NO and iloprostand were then randomized to 12.5 mg sildenafil, 50mg of sildenafil, 12.5 mg of sildenafil plus inhalediloprost, or 50 mg sildenafil plus inhaled iloprost.Best combination was 50 mg sildenafil plus iloprostfor reducing pulmonary vascular resistance andincreasing cardiac index. Iloprost alone plus 50 mgsildenafil alone were equally effective but less potentthan the combination.

Level of Evidence :High level.

◆◆◆

The effect of sildenafil on human vascular func-tion, platelet activation, and myocardial ischemia.Halcox JPJ, Nour KRA, Zalos G, et al. J Am CollCardiol 2002; 40:1232-1240.

Notes: Study of acute effects of sildenafil in patientsundergoing cardiac catheterization with normal coro-naries as well as patients with coronary artery disea-se. Sildenafil dilated epicardial coronaries by ~ 7%.Response to acetycholine and cold pressor testsimproved with sildenafil > in the CAD patients sug-gesting that sildenafil improves endothelial function.Platelet IIb/IIIa receptor activation was inhibited bysildenafil. In tests of endothelial dysfunction using

brachial artery dilation technique sildenafil prolon-ged the duration of hyperemia. Isosorbide dinitrateimproved myocardial ischemia during exercise tes-ting whereas sildenafil’s response was intermediatebetween placebo and nitrate.

Level of Evidence : High level.

◆◆◆

Effect of sildenafil on the acute pulmonary vasodi-lator response to inhaled nitric oxide in adults withprimary pulmonary hypertension. Lepore JJ, Maroo A, Pereira NL. Am J Cardiol2002; 90:677-680.

Notes: In nine patients with primary pulmonaryhypertension, sildenafil caused pulmonary vasodila-tion and improved cardiac index. When given withinhaled NO it augmented and prolonged the pulmo-nary vasodilator effects of NO and preventedrebound vasoconstriction.

Level of Evidence : High level.◆◆◆

Oral sildenafil is an effective and specific pulmo-nary vasodilator in patients with pulmonary arte-rial hypertension. Michelakis E, Tymchak W, Lien D, et al. Circula-tion 2002; 105:2398-2403.

Notes: Thirteen patients with pulmonary hyperten-sion had hemodynamic measures with inhaled NO,sildenafil or both. Sildenafil decreased pulmonaryvascular resistance and there was an additive effectwith iNO. Sildenafil improved cardiac index whe-reas iNO alone did not.

Level of Evidence :High level.

◆◆◆

Sildenafil (Viagra) induces powerful cardioprotec-tive effect via opening of mitochondrial KATPchannels in rabbits. Ockaili R, Salloum F, Hawkins J, et al. Am J Phy-siol Heart Circ Physiol 2002; 283:H1263-H1269.

Notes: In a rabbit model of myocardial infarctionsildenafil decrease blood pressure transiently, mar-kedly reduced myocardial infarct size when givenacutely before coronary occlusion or 24 hours befo-re coronary occlusion. Reasonable study but we’vebeen unable to reproduce these results in our lab.

Level of Evidence : High level.

◆◆◆

558

Intravenous sildenafil lowers pulmonary vascularresistance in a model of neonatal pulmonary hyper-tension. Shekerdemian L, Ravn HB, Penny DJ. Am J Res-pir Crit Care Med 2002; 165:1098-1102.

Notes: Animal study. Eighteen piglets in which pul-monary hypertension 2° to meconium aspiration ismimicked (as a cause of pulmonary hypertension inneonates). IV sildenafil completely reversed theincrease in pulmonary vascular resistance with noeffect on systemic hemodynamics.

Level of Evidence : High level.

◆◆◆

The effect of vardenafil, a potent and highly selec-tive Phosphodiesterase-5 inhibitor for the treatmentof erectile dysfunction, on the cardiovascular res-ponse to exercise in patients with coronary arterydisease. Thadani U, Smith W, Nash S et al. Journal of theAmerican College of Cardiology 2002;40(11):2002-2012.

Note: In this double-blind crossover, single-dosemulticentre study, 41 men with reproducible stableexertional angina due to ischaemic CAD receivedvardenafil 10 mg or placebo, followed by ETT (5 to10 metabolic equivalents [METS], Bruce protocol) 1hour postdose. At peak exercise, vardenafil 10 mgdid not alter blood pressure, heart rate, or rate pres-sure product relative to placebo. Vardenafil 10 mgdid not impair the ability of patients with stable CADto exercise at levels equivalent or greater than thatattained during sexual intercourse (average of 2.5 to3.3 METS).

Level of Evidence: High level

◆◆◆

The effect of vardenafil, a potent and highly selec-tive phosphodiesterase-5 inhibitor for the treatmentof erectile dysfunction, on the cardiovascular res-ponse to exercise in patients with coronary arterydisease. Thadani U, Smith W, Nash S, et al. J Am Coll Car-diol 2002; 40:2006-2012.

Supports: Addresses Question #5. CV safety ofvardenafil.

Notes: Double-blind, crossover, placebo controlledstudy of 41 men with stable exertional angina due toCAD who had exercise treadmill testing on a Bruceprotocol (5 - 10 Mets). Vardenafil did not alter exer-

cise time, or first awareness of angina. Vardenafilsignificantly prolonged time to ischemic threshold.Vardenafil did not alter blood pressure, heart rate, orrate - pressure - product.

Level of Evidence : High level.

◆◆◆

Effects of sildenafil citrate (Viagra) on blood pressu-re in normotensive and hypertensive men. Vardi Y, Klein L, Nassar S, et al. Urology 2002;59:747-752.

Notes: Sildenafil given to 22 hypertensive and 27normotensive men while ambulatory blood pressurewas monitored. Overall sildenafil decreased systolicby 6 mmHg and diastolic BP by -4.5 mmHg with nodifference in response between normotensive andhypertensive men. All men tolerated sildenafil wellwithout hypotensive symptoms event though 22.7%of hypertensive men and 4% of normotensive menhad a decrease in systolic BP of 20 mmHg or more.

Level of Evidence : High level.

◆◆◆

Immediate and long-term hemodynamic and clini-cal effects of sildenafil in patients with pulmonaryarterial hypertension receiving vasodilator therapy. Bhatia S, Frantz RP, Severson CJ et al. May ClinicProceedings 2003;78(10):1207-13.

Note: Sildenafil has an immediate pulmonary vaso-dilator effect in 13 patients already receiving vasodi-lators for pulmonary arterial hypertension but itslong-term effects on right heart function and functio-nal status are equivocal.

Level of Evidence: High level

◆◆◆

Effects of sildenafil (viagra) on human myocardialcontractility, in vitro arrhythmias and tension ofinternal mammaria arteries and saphenous veins. Cremers B, Scheler M, Maack C et al. Journal ofCardiovascular Pharmacology 2003;41(5)734-43.

Note: Sildenafil exerts potent vasodilatory actionsbut has no direct influence on human myocardialcontractility or proarrhythmic effects in vitro.

Level of Evidence: High level

◆◆◆

2003

559

The effects of sildenafil on the cardiovascular res-ponse in men with spinal cord injury at or above thesixth thoracic level. Ethans KD, Casey AR, Schryvers OI et al. TheJournal of Spinal Cord Medicine 2003;26:222-226.

Note: Large double blind placebo controlled crosso-ver trial of sildenafil 50 and 100 mg. Sildenafilinduces significant hypotension in people with cervi-cal-level injuries-more so than in thoracic-level inju-ries- and can cause dizziness in both populations. Itshould be prescribed with caution and informedconsent from the patient.

Level of Evidence: High level

◆◆◆

Sildenafil citrate does not reduce exercise tolerancein men with erectile dysfunction and chronic stableangina. Fox KM, Thadani U, Ma PT et al. European HeartJournal 2003;24(24):2206-12.

Note: Large study. Sildenafil was well tolerated anddid not adversely affect any exercise parameter inmen with coronary artery disease and ED. Favou-rable trends in total exercise duration and times toonset of angina and limiting angina were recordedwith sildenafil use.

Level of Evidence: High level

◆◆◆

Timecourse of the interaction between tadalafil andnitrates. Kloner Ra, Hutter Am, Emmick JT et al. Journalof the American College of Cardiology 2003;42(10):1855-60.

Note: Large cross-over study demonstrating the hae-modynamic interaction between tadalafil and sublin-gual nitroglycerin lasted 24 h, but was not seen at 48h and beyond. Similar to other PDE5 inhibitors, tada-lafil should not be administered in combination withorganic nitrates.

Level of Evidence: High level

◆◆◆

Clinical trials of sildenafil citrate (Viagra) demons-trate no increase in risk of myocardial infarctionand cardiovascular death compared with placebo. Mittleman MA, Glasser DB, Orazem J. InternationalJournal of Clinical Practice 2003;57(7):597-600.

Note: Meta-analysis of over 120 trials. The use of sil-denafil was not associated with an increase in the riskof MI or cardiovascular death (Pfizer sponsored).

Level of Evidence: High level◆◆◆

Effects of sildenafil on myocardial infarct size,microvascular function, and acute ischaemic leftventricular dilation. Reffelmann T, Kloner RA. Cardiovascular Resear-ch 2003;59(2)441-9.

Note: Open-chest rabbit study. Sildenafil reducedcardiac pre- and afterload, and parameters of leftventricular contractility. Myocardial necrosis andmicrovascular dysfunction were neither exacerbatednor attenuated.

Level of Evidence: High level

◆◆◆

Vascular effects of sildenafil in hypertensive car-diac transplant recipients. Schofield RS, Edwards DG, Schuler BT et al. Ame-rican Journal of Hypertension 2003;16(10):874-7.

Note: 15 patient study. Sildenafil (50 mg) is welltolerated in hypertensive cardiac transplant reci-pients and improves BP, aortic augmentation indexand endothelial function reducing left ventricularafterload and systolic stress.

Level of Evidence: High level

Evaluation of the safety of sildenafil for male erec-tile dysfunction: experience gained in general prac-tice use in England in 1999. Boshier A, Wilton LV, Shakir SAW. British Journalof Urology 2004;93:796-801.

Note: Large study of 22,471 men identifying thesafety profile of sildenafil as used in the community,showing no unexpected events. The standardizedmortality ratio analysis of deaths from IH providedno evidence to suggest a higher incidence of deathsin the study cohort than in the male population inEngland.

Level of Evidence: High level

◆◆◆

Efficacy and safety of sildenafil citrate in men witherectile dysfunction and stable coronary arterydisease. DeBusk RF, Pepine CJ, Glasser DB et al. Ameri-can Journal of Cardiology 2004;93(2):147-53.

Note: Large study, placebo-controlled. Sildenafil isan effective and well-tolerated treatment for ED inmen with CAD with no additional safety risks in thispatient population.

Level of Evidence: High level◆◆◆

2004

560

Clinical efficacy of sildenafil in primary pulmona-ry hypertension. A randomised, placebo-controlled,double-blind cross-over study. Sastry BKS, Narassimhan DM, Krishna Reddy N etal. Journal of the American College of Cardiology2004;43(7):1149-53.

Note: Randomised cross-over trial of sildenafil 25 to100 mg tds versus placebo. Sildenafil significantlyimproves exercise tolerance, cardiac index and QOLin patients with primary pulmonary hypertension.

Level of Evidence: High level

◆◆◆

Use of sildenafil for safe improvement of erectilefunction and quality of life in men with New YorkHeart Association classes II and III congestiveheart failure: a prospective, placebo-controlled,double-blind crossover trial. Webster LJ, Michelakis ED, Davis T et al. Archivesof Internal Medicine 2004;164(5):514-20.

Note: Large crossover trial of 35 patients. Sildenafilis a safe and effective treatment for ED in men withNew York Heart Association classes II and III CHFand provides relief of depressive symptoms, explai-ning an improvement in the perception of quality oflife.

Level of Evidence: High level

◆◆◆

Hypotensive interaction of sildenafil and nicorndilin rats through the cGMP pathway but not byKATP channel activation. Ishizuka N, Saito K, Akima M, et al. Jpn. J. Phar-macol 2000; 84:316-324.

Notes: Combination of sildenafil plus nicorandil orsildenafil with nitrates potentiates hypotension inpentobarbital anesthetized rats.

Level of Evidence : Intermediate level.

◆◆◆

Effects of sildenafil on human penile blood vessels. Medina P, Segarra G, Vila JM, et al. Urology 2000;56:539-543.

Note: Uses isolated penile dorsal arteries and deepdorsal veins from 14 multi-organ donors. Sildenafilcaused contraction dependent relaxation and ampli-fied relaxation to sodium nitroprusside. Relaxationwas unaffected by inhibitor of NO synthase.

Level of Evidence : Intermediate level.

◆◆◆

Relaxation induced by cGMP phosphodiesteraseinhibitors sildenafil and zaprinast in human ves-sels. Medina P, Segarra G, Martinez-Leon JB, et al.Ann Thorac Surg 2000; 70:1327-1331.

Note: In vitro study of human coronary, internalmammary, radial arteries, and forearm veins showingthat sildenafil caused concentration –dependentrelaxation in theses vessels. Sildenafil amplified theeffect of sodium nitroprusside.

Level of Evidence : Intermediate level.

◆◆◆

Sympathetic activation by sildenafil.Phillips BG, Kato M, Pesek CA, et al. Circulation2000; 102:3068-3073.

Note: Fourteen normal volunteers received sildena-fil vs. placebo. Sildenafil did not change HR, BP butdid increase muscle sympathetic activity and ↑ plas-ma norepinephrine levels and ↑ sympathetic nervetraffic during stress.

Level of Evidence : Intermediate evidence.

◆◆◆

2000

II : Intermediate Level Publications

561

Cardiovascular effects of sildenafil citrate(Viagra): A naturalistic cross-over study.Agelink MW, Schmitz T, Rembrink K, et al. Eur JMed Res 2001 6:459-564.

Note: Shows sildenafil ↓ resting BP (blood pressu-re), reflex ↑ in HR (heart rate), No change in ECG,HR variability. Suggests sildenafil does not affectcardiac autonomic nervous system function.

Level of Evidence : Intermediate level.

◆◆◆

Modulation of human platelet aggregation by thephosphodiesterase Type 5 inhibitor sildenafil.Berkels R, Klotz T, Sticht G, et al. Journal of Car-diovascular Pharmacology 2001; 37:413-421.

Note: 100 mg oral sildenafil increased bleeding timeat one hour after dose but bleeding time returned tobaseline at four hours. 50 mg dose had no effect. Invitro study showed that sildenafil 50 mg or 100 mgdid not inhibit ADP induced aggregation but colla-gen induced aggregation was reduced (note: differsfrom data shown in Pfizer AJC supplement).

Level of Evidence : Intermediate level.

◆◆◆

The effect of sildenafil on nitric oxide-mediatedvasodilation in healthy men. Dishy V, Sofowora G, Harris PA, et al. Clin Phar-macol Ther 2001; 70-270-279.

Note: In healthy men sildenafil increased sensitivi-ty to nitroglycerin 4 x but did not affect endothelium- dependent vasodilation in hand vein or forearmarterial vasculature. No data on men with ↓ endo-thelial function at baseline.

Level of Evidence : Intermediate level.

◆◆◆

Cardiovascular safety of sublingual apomorphinein patients on stable doses of oral antihypertensiveagents and nitrates. Fagan TC, Buttler S, Marbury T, Taylor A,Edmonds A; SL APO Study Group. Am J Cardiol2001 Oct 1;88(7):760-6.

Note: examined the pharmacodynamic interactionsbetween apomorphine SL and commonly used car-diovascular medications in a double-blind, crossoverstudy involving 162 men (mean age, 61 years) whohad been stable on therapeutic doses of ACE inhibi-tors, beta blockers, α1 blockers, calcium channelblockers, diuretics, or nitrates for at least four weeks.

Level of Evidence : Intermediate level.

◆◆◆

Nebulized sildenafil is a selective pulmonary vaso-dilator in lambs with acute pulmonary hyperten-sion. Ichinose, F, Erana-Garcia J, Hromi J, et al. Crit.Care Med. 2001 Vol. 29 5:1000-1005.

Note: Pulmonary hypertension induced by infusionof thromboxane analogue. Nebulized sildenafil ↓pulmonary artery pressures and had an additiveeffect with inhaled NO.

Level of Evidence : Intermediate level.

◆◆◆

Effect of sildenafil on blood pressure and arterialwave reflection in treated hypertensive men. Mahmud A, Hennessy M, and Feely J. Journal ofHuman Hypertension 2001; 15:707-713.

Note: Sildenafil given to eight men with wellcontrolled hypertension reduced brachial blood pres-sure and reduced arterial wave reflection.

Level of Evidence : Intermediate level.

◆◆◆

Potentiation of sildenafil-induced hypotension isminimal with nitrates generating a radical interme-diate. Schwemmer M, Bassenge E, Stoeter M, et al. Jour-nal of Cardiovascular Pharmacology 2001; 38:149-155.

Note: Chronically instrumented canine study. Twen-ty-four hour infusion of three types of nitrates andthen sildenafil. During glyceryl trinitrate sildenafil ↓BP 21 ± 13 mmHg; during ISDN -18 mmHg; duringpentaerythritol tetranitrate -6 mmHg.

Level of Evidence : Intermediate level.

◆◆◆

Cardiac phosphodiesterase 5 (cGMP-specific)modulates ββ-adrenergic signaling in vivo and isdown-regulated in heart failure. Senzaki H, Smith CJ, Juang GJ, et al. FASEB2001; 15:1718-1726.

Notes: This agent was used in conscious dog modelsincluding a heart failure model. They claim thatPDE5 is expressed in myocardial cells. PDE5Aregulation of cGMP is altered in heart failure andmay blunt the beta adrenergic response.

Level of Evidence : Intermediate level.

◆◆◆

2001

562

Assessment of the efficacy and safety of Viagra(sildenafil citrate) in men with erectile dysfunctionduring long-term treatment. Steers W, Guay AT, Leriche A, et al. InternationalJournal of Impotence Research 2001; 13:261-267.

Note: Open label study of sildenafil for efficacy (n =1008); not placebo controlled. Patients followed for36 or 52 weeks. Treatment related CV adverse events(↑ BP, tachycardia, palpitations, angina) < 1%.

Level of Evidence : Intermediate level.

◆◆◆

Effect of inhaled iloprost plus oral sildenafil inpatients with primary pulmonary hypertension. Wilkens H, Guth A, König J, et al. Circulation2001; 104:1218-1222.

Note: Small nonrandomized study showing that sil-denafil reduces pulmonary artery pressure in patientswith primary pulmonary hypertension and that thiseffect is additive with iloprost.

Level of Evidence : Intermediate level.

◆◆◆

Effect of Sildenafil on rennin secretion in humansubjects.Chiu YJ, Reid IA. Exp Bio Med 2002; 227:620-625.

Notes: Ten healthy human volunteers had unrestric-ted sodium intake; another 10 had restricted sodiumintake. Sildenafil had only minor CV effects. Plas-ma rennin activity was associated with a fall afterplacebo but no fall after sildenafil. Results regardingrenin similar between two groups. Significance ofthis study is not clear.

Level of Evidence : Intermediate level.

◆◆◆

Intracavernous injections for erectile dysfunctionin patients with cardiovascular diseases and failureor contraindications for sildenafil citrate. Israilov S, Niv E, Livne PM, et al. InternationalJournal of Impotence Research 2002; 14:38-43.

Notes: Success rate was 94% with injection therapy.Follow-up BPs in office did not show changes in bra-chial blood pressure or deterioration of CV health orchange in cardiac meds.

Level of Evidence :Intermediate level.

◆◆◆

Relaxation and cGMP formation in response to sil-denafil and sodium nitroprusside in saphenousveins from normotensive and hypertensive patients.Medina P, Segarra G, Martinez-Leon JB, et al. AmJ Hypertens 2002; 15:798-802.

Notes: Study of saphenous vein rings (in vitro) fromhypertensive and normotensive individuals. Sildena-fil caused venorelaxation that was greater in normo-tensives but had a synergistic effect with sodiumnitroprusside greater in veins of hypertensives. Sil-denafil ↑ cGMP levels.

Level of Evidence : Intermediate level.◆◆◆

Potential for use of pulse wave analysis in determi-ning the interaction between sildenafil and glyceryltrinitrate. O’Rourke MF, Nichols WW. Clin. Cardiol. 2002;25:295-299.

Notes: Central aortic wave form measured noninva-sively. Oral sildenafil augmented fall in aortic sys-tolic pressure in healthy volunteers. There was a fallin augmentation index and pulse pressure.

Level of Evidence : Intermediate level.

◆◆◆

Sildenafil and T-1032, phosphodiesterase type 5inhibitors, showed a different vasorelaxant proper-ty in the isolated rat aorta. Mochida H, Inoue H, Takagi M, et al. European J.of Pharmacology 2002; 440:45-52.

Notes: Study done in isolated rat aorta (in-vitro).Sildenafil caused vasodilation by both an ↑ in cGMPlevels as well as an inhibition of external calcium –dependent cascade.

Level of Evidence : Intermediate level.

◆◆◆

Effects of sildenafil citrate (Viagra) on cardiacrepolarizaton and on autonomic control in subjectswith chronic heart failure. Piccirrillo G, Nocco M, Lionetti M, et al. Am HeartJ 2002; 143:703-710.

Notes: In men with heart failure sildenafil decreasedvagal modulations plus ↑ sympathetic modulationswhich may have been secondary to reflex vasodilatoreffect. Sildenafil had no direct effect on QT intervalor dispersion. Nevertheless, authors conclude thatautonomic system changes could alter QT dynamicand favor arrhythmias.

Level of Evidence : Intermediate level.◆◆◆

2002

563

Interactions of sildenafil with various coronaryvasodilators in isolated porcine coronary artery. Sakuma I, Akaishi Y, Tomioka H, et al. EuropeanJournal of Pharmacology 2002; 437:155.163.

Notes: Study of isolated porcine coronary arteries inwhich interaction of sildenafil with various coronaryvasodilators was studied. Sildenafil potentiatedrelaxation of arteries to drugs that were NO donors.

Level of Evidence : Intermediate level.

◆◆◆

Sildenafil-nitric oxide donor combination promotesventricular tachyarrhythmias in the swine rightventricle.Swissa M, Ohara T, Lee M-H, et al. Am J PhysiolHeart Circ Physiol 2002; 282:H1787-1792.

Notes: Eight isolated swine right ventricles – vulne-rability to VT/VF tested by rapid pacing. No increa-se with sildenafil alone or NO donor alone, but com-bination increased incidence of VT/VF.

Level of Evidence : Intermediate level.

◆◆◆

Sildenafil reverses O2 constriction of the rabbitductus arteriosus by inhibiting type 5 phosphodies-terase and activating BKCa Channels. Thèbaud B, Michelakis E, Wu X-C, et al. PediatricResearch 2002; 52:19-24.

Notes: Fetal rabbit ductus arteriosus rings studiedin-vitro. Sildenafil induced dose-dependent relaxa-tion of the rings and might be an alternative or use-ful adjunct to prostaglandin E1.

Level of Evidence : Intermediate level.

◆◆◆

Sildenafil (Viagra) augments sodium nitroprussi-de-induced but not nitroglycerin-induced hypoten-sion in dogs. Yoo KY, Kim HS, Moon J-D, et al. Anesth Analog2002; 94:1505-1509.

Notes: Anesthetized canine preparation. Sodiumnitroprusside or nitroglycerin induced dose-depen-dent decreases in mean arterial blood pressurewithout affecting heart rate. Sildenafil augmentedthis effect with sodium nitroprusside but not nitro-glycerin. Results differ from other findings - perhapsanesthesia with thiopental blunted the effect.

Level of Evidence : Intermediate level.

◆◆◆

Sildenafil citrate does not affect QT intervals andQT dispersion: An important observation for drugsafety. Alpaslan M, Onrat E, Samli M et al. A.N.E.2003;8(1):14-17.

Note: Sildenafil does not prolong QT intervals orincrease QT dispersion in 36 patients with erectiledysfunction.

Level of Evidence: Intermediate level

◆◆◆

Oral sildenafil as long-term adjunct therapy toinhaled iloprost in severe pulmonary arterialhypertension. Ghofrani HA, Rose F, Schermuly RT et al. Journalof the American College of Cardiology 2003; 42(1):158-64.

Note: In 14 patients with severe pulmonary arterialhypertension deteriorating despite ongoing prosta-noid treatment, long-term adjunct oral sildenafilimproves exercise capacity and pulmonary haemo-dynamics at 9-12 months.

Level of Evidence: Intermediate level

◆◆◆

Sildenafil for long-term treatment of nonoperablechronic thromboembolic pulmonary hypertension. Ghofrani HA, Schermuly RT, Rose F et al. Ameri-can Journal of Respiratory 2003;167(8):1139-41.

Note: Chronic oral dosing at 6 months improved pul-monary haemodynamic and exercise capacity in 12patients. Possible important treatment option.

Level of Evidence: Intermediate level

◆◆◆

Haemodynamic effects of sildenafil in patients withstable ischaemic heart disease. Manfroi WC, Caramori PR, Zago AJ et al. Interna-tional Journal of Cardiology 2003;90(2-3):153-7.

Note: A single oral dose of sildenafil had no signifi-cant haemodynamic effect in 12 supine patients withstable angina. Isolated administration of sildenafildoes not appear to be associated to adverse cardio-vascular effects. Level of Evidence: Intermediate level

◆◆◆

2003

564

Effects of sildenafil on cardiopulmonary responsesduring stress. Stanopoulos I, Hatzichristou D, Tryfon S et al.Journal of Urology 2003;169(4):1417-21.

Note: Haemodynamic changes were minimal butmore in older patients with vasculogenic ED. 41patient study.Level of Evidence: Intermediate level

◆◆◆

Effects of sildenafil citrate (Viagra) on hemodyna-mic parameters during exercise testing and occur-rence of ventricular arrhythmias in patients witherectile dysfunction and cardiovascular disease. Vardi Y, Bulus M, Reisner S et al. European Uro-logy 2003;43(5)544-51.

Note: Sildenafil does not alter haemodynamic res-ponse to exercise or change incidence of ventriculararrhythmias in men with CVD and ED and should besafe for most patients with both these conditions.

Level of Evidence: Intermediate

◆◆◆

Erectile dysfunction in essential arterial hyperten-sion and effects of sildenafil: results of a SpanishNational Study. Aranda P, Ruilope LM, Calvo C et al. AmericanJournal of Hypertension 2004;17:139-145.

Note: An observational study of 2130 men withessential hypertension. Sildenafil showed an excel-lent response and safety profile.

Level of Evidence: Intermediate level

◆◆◆

Acute effects of sildenafil in patients with primarypulmonary hypertension receiving epoprostenol. Kuhn KP, Wickersham NE, Robbins IM, ByrneDW. Experimental Lung Research 2004; 30(2):135-145.

Note: Small study of 8 patients showing sildenafilhas greater acute haemodynamic effects than nitricoxide and that it can further reduce pulmonary vas-cular resistance in patients already demonstrating abenefit from chronic epoprostenol.

Level of Evidence: Intermediate level

◆◆◆

Hemodynamic response to sildenafil, nitric oxide,and iloprost in primary pulmonary hypertension. Leuchte HH, Schwaiblmair M, Baumgartner RA etal. Chest 2004;125(2):580-6.

Note: Small comparative study of 10 patients. All ofthe three substances, iNO, iloprost aerosol, and oralsildenafil, significantly improved pulmonary haemo-dynamics in patients with PPH. The most prominenthaemodynamic effects and improvement of oxyge-nation were observed with iloprost aerosol.

Level of Evidence: Intermediate level

◆◆◆

Clinical and haemodynamic effects of sildenafil inpulmonary hypertension: acute and mid-termeffects. Mikhail GW, Prasad SK, Li W et al Euro-pean Heart Journal 2004;25:431-6.

Note: Small study of 10 patients. Acute right heartand repeat study after 3 months of oral 50 mg tds.Pulmonary haemodynamics improved and quality oflife by questionnaire.

Level of Evidence: Intermediate level

◆◆◆

Sustained efficacy and tolerability with vardenafilover 2 years of treatment in men with erectile dys-function. Stief C, Porst H, Saenz De Tejada I et al. Interna-tional Journal of Clinical Practice 2004;58:230-9.

Note: Large study of 566 men with no cardiovascu-lar safety concerns.

Level of Evidence: Intermediate level

◆◆◆

2004

565

566