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Erectile dysfunction: Comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil - Review of the literature

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Since introduction of the PDE-5 inhibitor sildenafil 4 years ago, there has been a fundamental change in the treatment of erectile dysfunction (ED). Intracavernosal or intraurethral injections of vasoactive substances or penile implants as mechanical aids now play hardly any part in it. - The development of the PDE-5 inhibitors vardenafil and tadalafil prompts the question of whether and how these three substances differ in terms of their efficacy and adverse effects. - Sildenafil has proven to be a very effective medicinal product. Studies with a follow-up period of up to 6 years have been conducted. The success rate of sildenafil varies in the group of ED patients with an organic underlying disease from 43% in patients who have undergone radical prostatectomy to 85% in patients with a neurological underlying disease, and amounts to an average 82% (range 43-85%, 100mg). - In an evaluation of spontaneous reports of deaths associated with sildenafil, the FDA concluded that there was no deducible evidence of an increase in the mortality rate among sildenafil users compared to the general population. In fact, fewer deaths associated in time with the ingestion of sildenafil were reported than might have been expected purely statistically on the basis of the normal mortality rate for men in this age group. - According to the initial studies conducted, vardenafil and tadalafil demonstrate efficacy data approximately comparable to those of sildenafil. As yet, insufficient data are available to evaluate the adverse effects of vardenafil and tadalafil, particularly their long-term use and use in high-risk groups. - Sildenafil has already been used by over 20 million men in over 110 countries and is one of the best-studied pharmacological substances available. This adventage in terms of knowledge and safety data makes sildenafil a safe and reliable treatment for patients with erectile dysfunction.
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EUROPEAN JOURNAL OF MEDICAL RESEARCH 435
Abstract:
Since introduction of the PDE-5 inhibitor
sildenafil 4 years ago, there has been a fundamental
change in the treatment of erectile dysfunction (ED).
Intracavernosal or intraurethral injections of vasoac-
tive substances or penile implants as mechanical aids
now play hardly any part in it.
The development of the PDE-5 inhibitors varden-
afil and tadalafil prompts the question of whether
and how these three substances differ in terms of
their efficacy and adverse effects.
Sildenafil has proven to be a very effective medici-
nal product. Studies with a follow-up period of up to
6 years have been conducted. The success rate of sil-
denafil varies in the group of ED patients with an or-
ganic underlying disease from 43% in patients who
have undergone radical prostatectomy to 85% in pa-
tients with a neurological underlying disease, and
amounts to an average 82% (range 43-85%, 100mg).
In an evaluation of spontaneous reports of deaths
associated with sildenafil, the FDA concluded that
there was no deducible evidence of an increase in the
mortality rate among sildenafil users compared to the
general population. In fact, fewer deaths associated in
time with the ingestion of sildenafil were reported
than might have been expected purely statistically on
the basis of the normal mortality rate for men in this
age group.
According to the initial studies conducted, vardena-
fil and tadalafil demonstrate efficacy data approxi-
mately comparable to those of sildenafil. As yet, insuf-
ficient data are available to evaluate the adverse effects
of vardenafil and tadalafil, particularly their long-term
use and use in high-risk groups.
Sildenafil has already been used by over 20 million
men in over 110 countries and is one of the best-
studied pharmacological substances available. This
adventage in terms of knowledge and safety data
makes sildenafil a safe and reliable treatment for pa-
tients with erectile dysfunction.
Key words: Sildenafil; vardenafil; tadalafil; erectile dys-
function
1. INTRODUCTION
According to epidemiological surveys, one in five
men experiences impaired erection. Although these
erection disorders have been used to be attributed
mainly to psychogenic causes, they are now known to
be mainly organic in origin, at least in the 50-plus age
group.
Sexual dysfunction used to be, and still is in many
societies, a taboo subject, and the scientific study of it
was not pursued as vigorously as that of other medi-
cal conditions. This situation only changed with the
market introduction of the first effective drug for the
treatment of erectile dysfunction, sildenafil.
Since an effective oral drug treatment for erectile
dysfunction has been available, treatments involving
intracavernosal or intraurethral injections of vasoac-
tive substances or penile implants as mechanical aids
now play hardly any part.
Sildenafil and the substances vardenafil and tadal-
afil, which were developed later, are known as PDE-
5 inhibitors. Sildenafil and vardenafil differ only min-
imally in terms of their structure, while tadalafil dif-
fers markedly from sildenafil and
vardenafil in terms of its molecular structure, which
is also reflected in pharmacokinetic differences.
The development of the PDE-5 inhibitors varden-
afil and tadalafil now prompts the question of wheth-
er and how these three substances differ in terms of
efficacy and adverse effects from sildenafil.
Since few full publications about tadalafil and var-
denafil have been published, abstracts and poster
publications will also be considered in the followig
review.
Because patients ask for efficacy and side-effects
of the new substances being informed by marketing
reports in newspapers it is time to write this review
now, based on the informations available for the pub-
lic.
2. ERECTILE DYSFUNCTION
October 29, 2002
Eur J Med Res (2002) 7: 435-446
©
I. Holzapfel Publishers 2002
ERECTILE DYSFUNCTION:
COMPARISON OF
EFFICACY AND
SIDE EFFECTS OF THE
PDE-5 INHIBITORS
SILDENAFIL
, VARDENAFIL AND
TADALAFIL
R
EVIEW OF THE L
ITERATURE
U. Gresser
1
, C. H. Gleiter
2
1
Praxisklinik Sauerlach, Internal Medicine, Germany,
2
Department of Clinical Pharmacology, University of Tübingen, Germany
2.1. P
HYSIOLOGY OF
ERECTIONS
The physiological process of erection is based on the
interplay of neural, neurochemical and endocrinologi-
cal mechanisms (Sachs 2000). The smooth muscle
tone of corpus cavernosum and vascular system is
controlled by complex biochemical processes, regu-
lated by the peripheral and central nervous system.
This takes place via neuroanatomical connections
that constitute part of the innervation of the lower
urogenital tract (Moreland et al. 2001).
In the healthy man, sexual stimulation triggers a
release of the neurotransmitter nitric oxide (NO)
from non-adrenergic, non-cholinergic (NANC) neu-
rones that innervate the corpus
cavernosum of the penis. NO effects intracellular ac-
tivation of guanylate cyclase, which regulates the con-
version of 5-GTP to 3`,5`-cGMP. cGMP mediates
intracellular signal transduction, which leads via pro-
tein activation mechanisms to a reduction in the
intracellular Ca
++
concentration and so to relaxation
of the smooth muscles in
the penis, producing vasodilation and erection
(Moreland et al. 2001).
2.2. DEFINITION AND
CLASSIFICATION OF
E
RECTILE
DYSFUNCTION
According to the internationally recognised defini-
tion of the National Institute of Health (NIH) in
1993, Erectile Dysfunction (ED) is defined as the
persistent inability of a man to achieve and/or main-
tain an erection sufficient for a satisfactory sexual
performance (NIH Consensus Statement of
Impotence 1993).
ED can be classified according to its aetiology or
severity. From an aetiological viewpoint, a distinction
is made between an organic and psychogenic form,
with the organic form being further differentiated ac-
cording to vascular, neurogenic, anatomical and en-
docrinological causes. With the psychogenic form, a
distinction is made between generalised and situa-
tion-dependent ED (Lizza and Rosen 1999). Besides
a purely organic or purely psychological origin, mixed
forms combining both causes frequently exist, and
certain classes of drugs (e.g. beta-blockers, SSRI’s,
diuretics, etc) are also regarded as triggers of ED
(Meinhardt et al. 1997). Erection disorders are sub-
divided into mild, moderate, or severe ED, according
to the severity of the symptoms.
2.3. PREVALENCE OF ERECTILE DYSFUNCTION
The Massachusetts Male Aging Study (Feldman et al.
1994) found an ED prevalence of 52 % in 40 – 70-
year-old men. Another US study (Laumann et al.
1999), the “National Health and Social Life Survey”,
noted that 31% of men in the 18 - 60 year age group
had already experienced ED. In the German
“Cologne Male Survey” (Braun et al. 2000), a signifi-
cant age-correlated increase of 10% in the incidence
of ED was found in men between the ages of 40 and
49, 16% in men between 50 and 59, 34% in men
between 60 and 69, and over 50% in men between 70
and 80 years of age. The overall prevalence (age range
30-80 years) was 19.2%. Studies in England and
France have yielded similar results (Spector and Boyle
1986, Giuliano et al. 1996). These results mean that
almost one in five men experiences erectiles dysfunc-
tion.
Contrary to the earlier view that the cause of ED is
predominantly psychogenic, it is now known to be
due mainly to organic dysfunctions, at least in the 50-
plus age group (Kaiser 1999).
2.4. CAUSES OF
ERECTILE
DYSFUNCTION
In most cases, erectile dysfunction is due to several
causes. Cardiovascular risk factors are the most im-
portant. According to the Cologne study (Braun et al.
2000), 20% of ED patients suffer from diabetes mel-
litus, 30% from arterial hypertension, 30% are smok-
ers and 38% regularly consume alcohol.
Similar results were also found by Pritzker
(Pritzker 1999). According to his studies, 20% of ED
patients show undiagnosed diabetes mellitus, 48% hy-
pertension and 70% raised cholesterol levels.
Similarly, Roumeguère et al. (2001) found diabetes
mellitus in 20% of ED patients, hypertension in 26%,
and hyperlipidaemia in 76%.
2.5. THERAPEUTIC
OPTIONS FOR
ERECTILE
D
YSFUNCTION
The first objective of every doctor is to cure the med-
ical condition. Therefore, the primary goal in ED
treatment is to determine the aetiology of the disease
and treat it when possible, and not to treat the symp-
tom alone. (Wespes et al. 2002). Nevertheless, it has
been shown that treatment of organic risk factors
alone often does not significantly improve the pa-
tient´s erectile function (Montorsi et al. 2002).
Oral drug treatments, the use of an erection-sup-
porting vacuum pump and/or psychological sex ther-
apy are symptom-orientated treatments available for
erectile dysfunction (Montorsi et al. 2002). If none of
these brings the desired success, treatment with intra-
cavernosal or intraurethral injections of vasoactive
substances can be attempted as second-line treat-
ments (Montorsi et al. 2002). However, most patients
find this a very unpleasant experience. Penis implants
as mechanical aids play hardly any part in treatment
since the introduction of sildenafil.
There are various approaches in drug treatment,
which differ significantly in terms of their clinical ef-
ficacy.
For local use with intraurethral or intracavernosal
injection (corpus cavernosum auto-injection therapy),
the synthetic prostaglandin analogue (PGE1) alpros-
tatil, for example, can be used. This treatment pro-
duces an erection by increasing the cAMP level in the
corpus cavernosum (Andersson 2001).
In terms of oral therapeutic options, a fundamen-
tal distinction is made between a central and a pe-
ripheral action site.
The centrally acting substances available are the
dopamine receptor agonist apomorphine and the se-
lective alpha2 adrenoceptor blocker yohimbine.
EUROPEAN JOURNAL OF MEDICAL RESEARCH436 October 29, 2002
Yohimbine acts both centrally as a noradrenergic ag-
onist and peripherally as an alpha2 adrenoceptor
blocker (Hatzichristou 2001). It has not yet been pos-
sible to demonstrate significant efficacy above the
placebo level in a robust study. Accordingly, yohim-
bine has been classified as inadequately effective for
the treatment of organic ED in the guidelines of the
American Urology Association (Montague et al.
1996).
Apomorphine produces its effect by stimulating
central dopamine receptors (predominantly D2) in
the paraventricular nucleus of the hypothalamus,
which activates pro-erectile pathway systems (includ-
ing NO and oxytocin) and in this way produces an
erection (Hatzichristou 2001). In a double-blind, pla-
cebo-controlled study by Dula et al. (2001), an erec-
tion firm enough for intercourse was obtained in 46.9
% of ED patients on apomorphine treatment, com-
pared with a baseline figure of 21.9 %. In comparison
with the placebo rate of 32.3 %, there is an absolute
improvement of 14.6 %, which is not a satisfactory
result. This is also evident in the low market share for
apomorphine preparations, which in the case of
Europe is less than 5 % (IMS data as at April 2002).
The most effective form of oral treatment are
phosphodiesterase inhibitors, which will therefore be
discussed in greater detail.
3. PHOSPHODIESTERASES AND THEIR
INHIBITORS
To date, 11 PDE groups (PDE 1-11) are known, and
these can be further differentiated into 21 sub-groups
and about 53 splice variants.
Since these PDE forms are involved in the most
diverse bodily functions in the form of in some cases
very similar molecules, this raises the question of
whether the PDE-5 inhibitors that are relevant to ED
treatment also inhibit other phosphodiesterases.
Table 1 provides an overview of the distribution of
the PDE groups in the body and their possible func-
tions (Francis et al. 2001, Osterloh 2001).
3.1. MECHANISM OF
ACTION OF PDE-5 INHIBITORS
Phosphodiesterase inhibitors used for ED treatment
are selective, competitive inhibitors of phosphodies-
terase type 5 (PDE-5), an enzyme that breaks down
cyclic guanosine monophosphate (cGMP) in various
tissues, the second messenger of NO (Boolell et al.
1996). The selective and competitive PDE-5 inhibitor
is sildenafil. PDE-5 inhibitors potentiate the muscle-
relaxant effect of NO and are pharmacologically ac-
tive only where cGMP synthesis is activated (e.g.
through NO) (Ballard et al. 1998, Jeremy et al. 1997).
Following sexual stimulation, NO is released in the
corpus cavernosum from nerves, vascular endotheli-
um and smooth muscle cells, as a result of which the
vessels in the penis and corpus cavernosum dilate,
producing an erection (Burnett 1997). By inhibiting
cGMP breakdown, PDE-5 inhibitors enhance the
vasodilatory effect of NO and restore the ability to
achieve an erection in patients with erectile dysfunc-
tion.
3.2. PHOSPHODIESTERASE FAMILY
PDE-5 is a member of the phosphodiesterase family,
which regulates multiple cell functions throughout
the human body, by catalysing the breakdown of
cGMP and cAMP. cGMP and cAMP are molecules of
intracellular signal transduction that lead to protein
phosphorylation, modulation of enzymes, ion chan-
nels, receptors and contractile proteins, through acti-
vation of protein kinase G.
The major function for phosphodiesterases in the
cell is to terminate the cyclic nucleotide second mes-
senger signal (Beavo et al 1995).
The cGMP level is a critical parameter for many
cell functions, and is strictly regulated by a variety of
control circuits in which phosphodiesterases play a
central role. Much about this remains unexplained.
PDE-5 activity is controlled by at least two regula-
tory pathways.
The gene for all of the isoforms of PDE-5 known
to date (A1-A2-A3) is found on chromosome 4q26
(Loughney et al. 1998, Yanka et al. 1998). In studies
with human corpus cavernosum cell cultures, Lin et
al were able to demonstrate that an increase in cGMP
levels over 48 hours increases the activity of the
PDE5A promoter gene and therefore PDE-5 expres-
sion or PDE-5 tissue levels (Lin et al. 2002).
Moreover, an increase in the cGMP level also leads
to an increase in catalytic PDE-5 activity, with cGMP
in conjunction with phosphokinase G and ATP lead-
ing to PDE-5 phosphorylation, which results in an
increase in the cGMP binding capacity. By means of
this mechanism, Corbin et al. (2000) were able to
demonstrate a 50-70% increase in catalytic PDE-5
enzyme activity after an incubation time of only 1
hour.
Besides the increase in PDE-5 expression and the
increase in catalytic activity (degradation pathway),
the cGMP level can also be regulated via a change in
cGMP synthesis. For example, Murthy was able to
show by means of cell culture experiments that an in-
creased cGMP level leads to a reduction in sGC syn-
thesis via phosphokinase G-mediated phosphoryla-
tion of soluble guanylate cyclase (sGC) (Murthy et al.
2001).
On the basis of these results, the following hy-
pothesis regarding the regulation of cGMP levels
would be conceivable:
An increase in the cGMP level (e.g. through pro-
longed PDE-5 inhibition) leads to an increase in
cGMP breakdown via an increase in PDE-5 activity
and expression, and to a reduction in cGMP produc-
tion via a reduction of sGC activity. The mechanisms
described here then might lead to a reduction in the
cGMP level in the form of counter-regulation.
Owing to the lack of sufficient long-term data, it is
not yet possible to judge whether or not clinically rel-
evant pharmacodynamic habituation occurs as a re-
sult of a chronic increase in the cGMP level, such as
through the use of long-acting PDE-5 inhibitors like
tadalafil.
Interesting long-term data for repeated use exist on
EUROPEAN JOURNAL OF MEDICAL RESEARCHOctober 29, 2002 437
the assessment of the substance sildenafil. Sildenafil
has been used in German clinical trials since 1995. In
England, a small group of diabetes patients was treat-
ed for 6 years; 10 out of 11 were still very pleased with
the success of the treatment 6 years later (Price 1999).
In other studies, the long-term efficacy and tolerance
of sildenafil were studied over a period of up to 3
years; 87-96% of ED patients proved to be pleased
with sildenafil treatment, and the discontinuation rates
due to lack of efficacy were, at 1-9%, very low
(Montorsi et al. 2001, Steers et al. 2001, Gingell et al.
1999, Hackett 1999, Guliano et al. 1997, Christiansen
et al. 2000, Hackett and Milledge 2001), so, at least for
PDE-5 inhibitors with a relatively short half-life such
as sildenafil, there is no evidence of a clinically rele-
vant habituation effect.
3.3. CHEMICAL
STRUCTURE OF C
GMP AND THE PDE-5
I
NHIBITORS SILDENAFIL, VARDENAFIL AND TADALAFIL
As competitive inhibitors of PDE-5, the chemical
structures of the substances (Fig. 1) are very similar to
that of cGMP. Sildenafil and vardenafil differ only
minimally in terms of their structure, as a direct com-
parison of the structural formulas shows.
Tadalafil differs markedly from sildenafil and var-
denafil in terms of its molecular structure, which is
also reflected in marked pharmacokinetic differences.
3.4. P
OTENCY AND SELECTIVITY OF
PDE-5
I
NHIBITORS
A review of the literature shows that the measured
values for the potency and selectivity of PDE-5 in-
hibitors can vary, which can be demonstrated , for ex-
ample, by the IC
50
values (concentration at which the
enzyme activity is 50% inhibited) of sildenafil (Table
2).
The reason for this is that IC
50
values are depen-
dent on the cGMP concentration, the source and ex-
traction method of the enzymes, the reaction condi-
tions, the number of samples, and other factors in the
experimental design (Osterloh 2001). For this reason,
different laboratories may obtain differing measure-
EUROPEAN JOURNAL OF MEDICAL RESEARCH438 October 29, 2002
Table 1. Distribution and function of phosphodiesterases (Francis et al. 2001, Osterloh 2001)
PDE isoenzyme/ Tissue distribution Possible functional significance of PDE
substrate
PDE 1 / Brain, heart, skeletal muscles, Vascular muscular weakness, taste,
cGMP liver, vascular muscles, visceral muscles olfaction
cAMP
PDE 2 / Adrenal cortex, corpus cavernosum, heart, Olfaction, adrenocorticosteroid
cGMP visceral muscles, brain, skeletal muscles production
cAMP
PDE 3 / Corpus cavernosum, heart, vascular and Myocardial contractility; insulin
cGMP visceral muscles, blood platelets, liver, secretion; lipolysis, glucoseproduction,
cAMP adipose tissue, kidney platelet aggregation
PDE 4 / Brain, testes, thyroid gland, kidney, lung, Inflammation; vascular and visceral
cAMP mast cells, skeletal muscles, vascular and muscle tone; depression, thyroid
visceral muscles gland secretion, reproduction
PDE 5 / Corpus cavernosum, vascular and visceral Erection; smooth muscle tone
cGMP muscles, blood platelets platelet aggregation
PDE 6 / Retina (cones, rods) Signal transduction in vision
cGMP
PDE 7 / Skeletal muscles, heart, lymphocytes T-cell activation; skeletal muscles;
cAMP metabolism
PDE 8 / Widespread; e.g. testes, ovaries, bowel T-cell activation
cAMP
PDE 9 / Widespread; most strongly expressed in ?
cGMP the spleen, small intestine and brain
PDE 10 / Brain (putamen and caudal nerve), testes, Dopamine signal transmission
cGMP thyroid gland
cAMP
PDE 11 / Skeletal muscles, heart, vascular muscles ?
cGMP and visceral muscles (corpus cavernosum,
cAMP prostate), pituitary gland, testes, liver and
kidneys
ment results, depending on the study conditions se-
lected.
This lack of measurement precision concerns all
PDE-5 inhibitors. The IC
50
of tadalafil in terms of
PDE-5 has been calculated as between 0.9 nM
(Angulo et al. 2001) and 6.7 nM (Baxendale et al.
2001) and the IC
50
of vardenafil between 0.1 nM
(Philips et al. 2002) and 0.7 nM (Saenz de Tejada et
al. 2001). Accordingly, vardenafil exhibits an PDE-5
inhibitory potential approximately five times higher
than that of sildenafil , which is also reflected in the
dosages used in clinical trials (5, 10 or 20 mg vardena-
fil versus dose strengths of 25, 50 and 100 mg silden-
afil). For the assessment of efficacy and tolerance, it
is therefore important to use equipotent dosages, i.e.
to compare 20 mg vardenafil with 100 mg sildenafil,
for example.
A single oral dose of 100 mg sildenafil produces a
mean peak free sildenafil plasma concentration of 38
nM (EU-SPC VIAGRA). In order to achieve an inhi-
bition of some 90 % in PDE–5 activity, a free drug
concentration of approximatelly 25 nM is necessary
(Turko et al. 1999). PDE-5 is therefore already maxi-
mally inhibited by administration of 100 mg sildenafil
(Gopal et al. 2001). This applies both in resting con-
ditions and on stimulation of cGMP synthesis (e.g.
through sexual activity). With this high efficacy, sil-
denafil sets the standard for other substances.
In relation to the binding potency of individual
PDE-5 inhibitors to other PDE isoenzymes, there are
no clear significant differences.
Considering selectivity for PDE 1-4 and 7-10 ver-
sus PDE-5, the substances discussed here show no
relevant differences (Table 3).
Differences are apparent in terms of PDE-6,
which plays an important role in the conversion of
light impulses into nerve impulses in the retina. Here,
sildenafil and vardenafil show lower selectivity than
tadalafil. However, since peak plasma levels of 970
nM are reached after administration of 20 mg tadala-
EUROPEAN JOURNAL OF MEDICAL RESEARCHOctober 29, 2002 439
Sildenafil Vardenafil
cGMP Tadalafil
Fig. 1. Chemical structure of
cGMP and the PDE-5 inhibitors
sildenafil, vardenafil and tadala-
fil.
fil (Patterson et al. 2001), it remains to be seen
whether or not PDE-6 might be inhibited by these
substance under clinical conditions, something which
cannot currently be assessed in view of the lack of
published data on plasma protein binding and the
free fraction.
A further difference exists in the area of PDE-11.
Here tadalafil shows only 5 times greater selectivity
with respect to PDE-5, which indicates inhibition of
PDE-11 by tadalafil at clinical doses (Baxendale et al.
2001). PDE-11 inhibition by tadalafil could lead to
adverse effects in clinical use. So far, PDE-11 has
been detected in a variety of human tissues, e.g. in the
heart, pituitary gland, brain and testes. The physio-
logical significance of PDE-11 and the possible con-
sequences of its inhibition have not yet been estab-
lished. There is a marked difference of tadalafil ver-
sus sildenafil and vardenafil. Sildenafil and vardenafil
are not expected to inhibit PDE-11.
3.5. P
HARMACOKINETICS
All three substances are rapidly absorbed from the
gastrointestinal tract, with peak plasma levels being
attained within 1 hour in the case of sildenafil
(Milligan et al. 2002) and vardenafil (Sachse and
Rohde 2000) and after 2 hours in the case of tadalafil
(Patterson et al. 2001), with a range of 0.5 – 12 hours
for tadalafil. Absorption takes place mainly from the
small intestine, with the gastric emptying time playing
an important role in the onset of action.
According to the current publication situation,
food intake causes no delay or reduction in tadalafil
absorption (Ibid 2001), whereas it is known to reduce
and delay sildenafil absorption (Nicols et al. 2002).
Since, at a therapeutic dosage, sildenafil has adequate
latitude in terms of maximum inhibition of PDE-5, a
good clinical effect is also obtained on ingestion after
food intake. Ingestion on an empty stomach produc-
es a more rapid onset of action, whereas ingestion
after or with a meal produces a slower onset of action
(Corbin and Francis 2002).
The bioavailability of sildenafil is approx. 41 %
(Nichols et al. 2002). After a single oral dose of 100
mg sildenafil, a total mean plasma concentration of
approximatelly 440 ng/ml is achieved, the plasma
protein binding is 96 %, which means that there is a
mean free sildenafil peak plasma concentration of 18
ng/ml. For tadalafil (20 mg) and vardenafil (20 mg)
total mean plasma concentrations are 378 ng/ml
(Patterson et al. 2001) respectively 19 ng/ml (Sachse
and Rhode 2000). Data concerning plasma protein
binding or mean free peak plasma concentrations
have not yet been published.
The mean half-lives of sildenafil and vardenafil are
3 - 4 hours (Sachse and Rohde 2000) and that of ta-
dalafil, approximatelly 18 hours (Patterson et al.
2001). Tadalafil can still be detected in the blood 5
days after ingestion (Patterson et al. 2001), which
means that accumulation might be possible, if tadala-
fil would be taken regularyly and in short intervals.
Approximatelly 50 % of all drugs are metabolised
via the cytochrome-P 450 system (Eichelbaum and
Burk 2001), which exhibits a great deal of genetic
polymorphism. The elimination of sildenafil (Hyland
et al. 2001), vardenafil (Rohde et al. 2001) and tadala-
fil ((Patterson et al. 2001) takes place overwhelmingly
EUROPEAN JOURNAL OF MEDICAL RESEARCH440 October 29, 2002
Table 2. IC
50
P values of sildenafil according to analyses by
various laboratories.
Laboratory IC
50 of
sildenafil
Ballard et al. 1998 3.5 nM
Turko et al. 1999 4 nM
Saenz de Tejada et al. 2001 6.6 nM
Bischoff et al. 2001 8.5 nM
Table 3. Selectivity of sildenafil, vardenafil and tadalafil with reference to the various PDE groups (Phillips et al. 2002, Ballard
et al. 1998).
PDE groups Sildenafil IC
50
Vardenafil IC
50
Tadalafil IC
50
Nmol (x fold selectivity) Nmol (x fold selectivity) Nmol (x fold selectivity)
PDE1 281 (80) 70 (500) >30000 (>4450)
PDE2 >30000 (>8570) 6200 (44290) >100000 (>14800)
PDE3 16200 (4630) >1000 (>7140) >100000 (>14800)
PDE4 7680 (2190) 6100 (43570) >100000 (>14800)
PDE5 3.5 (1) 0.14 (1) 6.7 (1)
PDE6 (rods) 37 (11) 3.5 (25) 1260 (187)
PDE6 (cones) 34 (10) 0.6 (4) 1300 (193)
PDE7A 21300 (6090) >30000 (>214000) >100000 (>14800)
PDE8A 29800 (8510) >30000 (>214000) >100000 (>14800)
PDE9A 2610 (750) 581 (4150) >100000 (>14800)
PDE10A 9800 (2800) >3000 (>21200) >100000 (>14800)
PDE11A 2730 (780) 162 (1160) 37 (5)
via the liver, mostly via the cytochrome enzyme P450
(CYP3A4). CYP3A4 expression varies up to a factor
of 50 between various individuals, and in vivo en-
zyme function by at least a factor of 20 (Özdemir et
al. 2000).
4. CLINICAL EXPERIENCE
4.1. ONSET OF
EFFECT AND D
URATION OF EFFECT
In humans, the mean onset of effect of sildenafil
takes place approximately 27 min. after ingestion
(Eardley et al. 2002); in the rabbit vardenafil acts ap-
prox. 20 min. afterwards, the maximum vardenafil ef-
fect takes place after 45 to 90 min. (Bischoff et al.
2001).
An initial onset of action 16 min. after ingestion
has been described for tadalafil in a highly preselect-
ed population (Padma-Nathan et al. 2001); for sil-
denafil, too, efficacy has been demonstrated only 12
minutes after ingestion (Eardley et al. 2002). Peak
plasma tadalafil levels (Patterson et al. 2001) are
reached after two hours on average.
In one study of tadalafil (25 mg) in 61 men, adequate
efficacy was found in the majority of patients after
30 to 120 min..However, 24 h after ingestion of ta-
dalafil (10 and 20 mg respectively) some effect was
still apparent (Padma-Nathan et al. 2001).
4.2. EFFICACY
According to the study results available to date, all
three PDE-5 inhibitors are effective.
Owing to the lack of direct comparative studies,
any comparison of the clinical effect of the substanc-
es relies on the comparison of different, not directly
comparable, studies, which is difficult because the
target criteria and patient selection criteria are not
uniform.
In some cases, sildenafil non-responders were ex-
cluded from studies with vardenafil (Porst et al. 2001,
Brock et al. 2001) and tadalafil (Brock et al. 2002),
which makes it practically impossible to compare re-
sponse rates. For this reason, a sensible comparison
criterion would appear to be a change in erectile
function versus the baseline value in comparison with
placebo, which was recorded uniformly in all of the
studies using the IIEF questionnaire (IIEF =
International Index of Erectile Function).
Treatment with vardenafil in a dose of 20 mg pro-
duced an improvement in the ability to achieve an
erection in 80 % of ED patients (Porst et al. 2001).
In a comparable study of sildenafil (100 mg dose) by
Goldstein, 84 % of ED patients were successfully
treated (Goldstein et al. 1998). Treatment with tadal-
afil 25 mg produced an improvement in the ability to
achieve an erection in 81 % of ED patients (Padma-
Nathan et al. 2001). Therefore, sildenafil, at 84 %, is
slightly more effective than vardenafil at 80 % and
tadalafil at 81 %. If efficacy is compared versus pla-
cebo, the differences between sildenafil and the two
other substances are even clearer. In comparison
with placebo, treatment with 100 mg sildenafil leads
to a 20-fold improvement in IIEF question 3 (when
you attempted sexual intercourse, how often were
you able to penetrate your partner?), treatment with
20 mg vardenafil to a 7.5-fold improvement, and
treatment with 25 mg tadalafil to a 1.4-fold improve-
ment compared to initial value.
4.3. TOLERANCE
Typical side effects of PDE-5 inhibitors are head-
ache, facial flushing, nasal congestion, and dyspepsia.
According to the current publication situation, de-
sired and undesired effects can be assumed to be
similarly frequent, similarly severe and similarly
dose-dependent for all three PDE-5 inhibitors. As
yet, the published data on the two more recent sub-
stances remain insufficient to reach a conclusive as-
sessment of the adverse effects. In particular, there is
a lack of large, double-blind, randomised compara-
tive studies. It would be particularly interesting to es-
tablish whether the relatively long elimination half-
life of
tadalafil or the low bioavailability of vardenafil is as-
sociated with a greater number of adverse effects.
Both sildenafil and vardenafil weakly inhibit PDE-
6. Changes in vision have been described - rarely - for
both substances in relatively high dosages (Porst et al.
2000, Sachse and Rohde 2000). Experience with sil-
denafil has shown that only a few patients discontin-
ue treatment for this reason (Laties et al. 2000,
Zrenner et al. 2000). Long-term studies with sildena-
fil have produced no evidence of more extensive or
permanent disturbances of the visual system as a re-
sult of occasional PDE-6 inhibition (Wallis et al.
1998, Grunwald et al. 1999). Similar data is not yet
available for vardenafil. In the case of sildenafil, pa-
tients with retinitis pigmentosa, a rare hereditary dis-
ease, are excluded from treatment for drug safety rea-
sons.
Tadalafil is a potent PDE-11 inhibitor , found,
amongst other places, in the smooth muscles of the
internal organs, cardiac and skeletal muscles, pituitary
gland, Leydig’s cells and germ cells in the testes
(Baxendale et al. 2001, Osterloh 2001). The physio-
logical significance of the enzyme and the possible
consequences of its short-term or medium-term inhi-
bition have not yet been established. The back and
muscle pain reported relatively frequently with tadal-
afil (Porst 2000) may be associated with this.
Tolerability of tadalafil is problematic: with daily
ingestion, 7 % of patients in the 10 mg group discon-
tinued treatment owing to side effects, 10 % at 25
mg, 19 % at 50 mg and 29 % at 100 mg. With inges-
tion on demand, tadalafil caused muscle and back
pain in over 10 % of those treated and dyspepsia and
headache in over 25 % (Porst 2000).
4.4. INTERACTIONS
All PDE-5 inhibitors act in a similar way via the
NO/cGMP mechanism described at the beginning.
For this reason, tadalafil and vardenafil can be as-
sumed to potentiate the hypotensive and anticoagu-
lant effect of nitrates and NO donors, as is already
known to occur with sildenafil. Vardenafil and tadala-
EUROPEAN JOURNAL OF MEDICAL RESEARCHOctober 29, 2002 441
fil potentiate the vasodilatory effect of NO donors
(Angulo et al. 2001a and b, Bischoff et al. 2001). In
patients who are being treated with them, none of the
three PDE-5 inhibitors is advisable.
For sildenafil detailed informations are published
in the Standard Product Characteristics (EU-SPC
Viagra).
Since all 3 substances are broken down mainly via
cytochrome P450 CYP3A4, a dose adjustment should
be considered when given in combination with
CYP3A4 inhibitors (e.g. HIV protease inhibitors,
erythromycin, ketoconazole).
4.5. H
IGH-RISK GROUPS
Like sildenafil, vardenafil has a slightly hypotensive
effect, maximal 5-10 mmHg average (Sachse and
Rohde 2000). An increase in the heart rate has been
described at a vardenafil dose of 40 mg (Sachse and
Rohde 2000).
Since peak vardenafil levels are 30 % higher in eld-
erly patients and the half-life is 25 % longer (Porst et
al. 2001), low dosages should first be used in this pa-
tient group. At the high dose of 20 mg vardenafil, ad-
verse effects were reported twice as frequently in eld-
erly patients with 63 % (Porst et al. 2001).
Tadalafil, too, exhibits a 28 % longer half-life, i.e.
22 hours, in elderly patients. In elderly men, the sub-
stance was still detectable 6 days after ingestion.
Impaired hepatic and renal function also produced an
additional lengthening of the half-life of the sub-
stance. Furthermore, smoking and the body mass
index had a weak effect on the pharmacokinetics of
tadalafil (Patterson et al. 2001) whereas food intake
had no effect (Patterson et al. 2001).
Both diabetes mellitus and sexual intercourse are
associated with an increased risk to get a cardiovascu-
lar event. For vardenafil serious adverse events have
been reported in diabetes patients (placebo: 1 %, 10
mg: 2 %, 20 mg: 3 %) (Goldstein et al. 2001).
The availability of the new PDE-5 inhibitors has
led to an intensive discussion of the differences in ef-
ficacy and the side effect rate in comparison to sil-
denafil, particularly with respect to the frequency of
any cardiovascular events. In the first phase of the
Prescription Event Monitoring study, it became clear
that myocardial infarctions and deaths as a result of
coronary heart disease were not observed more fre-
quently in sildenafil users than in the general popula-
tion, even in widespread use - when prescribed by
doctors in general practice without any formal inclu-
sion and exclusion criteria (Shakir et al. 2001). Age-
standardised mortality and morbidity rates produce
no evidence of an increased risk of myocardial infarc-
tion or deaths as a result of coronary heart disease in
sildenafil patients.
In an FDA publication (Wysowski et al. 2002), a
conclusive evaluation of spontaneous reports of
deaths associated with sildenafil was undertaken. The
authority came to the conclusion that no evidence of
an increased mortality rate among sildenafil users
compared to the general population could be de-
duced from the spontaneous reports. In fact, fewer
deaths associated in time with the ingestion of sil-
denafil were reported than might have been expected
purely statistically on the basis of the normal mortal-
ity rate for men in this age group.
4.6. C
ONTRAINDICATIONS
For all three substances contraindications are similar.
Patients in whom sexual activity is not advisable
on medical reasons (e.g. patients with severe cardio-
vascular disease) should not be given ED treatment
(DeBusk et al. 2000). In some circumstances, abstain-
ing from sexual activity may save the lives of these
patients - even though they have to forego some of
the pleasure of sexual activity. For the same reason,
patients who have recently experienced a heart attack
or stroke should be excluded from ED treatment.
In patients receiving nitrate or NO-donors treat-
ment with PDE-5 inhibitors is contraindicated.
Since both sildenafil and vardenafil have moderate
vasodilatory and hypotensive effects, they should not
be given in the presence of marked arterial or orthos-
tatic hypotension, and should only be administered
with caution in aortic stenosis
or hypertrophic obstructive cardiomyopathy. Further
studies are needed to clarify whether tadalafil affects
the circulatory system less owing to its slower phar-
macokinetics.
Patients with retinitis pigmentosa should not be
treated with a PDE-5 inhibitor.
Patients receiving nitrate or NO-donor treatment,
and those who have experienced significant cardiac
events in the previous six months, suffer from pro-
liferative retinopathy or retinitis pigmentosa have
been excluded from studies with vardenafil
(Goldstein 2001, Porstet al. 2001, Klotz et al. 2001),
something which is scientifically logical and ethically
correct. Even more caution has been exercised in
studies with tadalafil - all patients with signs of clini-
cally relevant liver, kidney or coronary artery disease,
cardiovascular disease or CNS disturbances in the last
six months have been excluded (Porst 2000, Brock et
al. 2001).
This is to be acknowledged as morally and ethical-
ly positive, but it does make it more difficult to com-
pare the new substances with sildenafil, which -
being the first PDE-5 inhibitor in clinical use - has
been studied in considerably wider-ranging patient
populations. There are sufficient data on sildenafil to
confirm that it does not lead to
an increase in the mortality rate compared with the
general population (Wysowski et al. 2002). It is not
possible to comment on vardenafil and tadalafil in
this regard, owing to the lack of study data.
5. CONCLUSION
As knowledge stands at present, PDE-5 inhibitors are
the method of choice for the treatment of erectile
dysfunction, alongside treatment for the underlying
disease.
Sildenafil has proven to be an effective and well to-
lerated drug. Studies with a follow-up period of up to
4 years have been conducted. The success rate of sil-
denafil varies in the group of ED patients with an or-
EUROPEAN JOURNAL OF MEDICAL RESEARCH442 October 29, 2002
ganic underlying disease between 43% in patients
who have undergone radical prostatectomy and 85%
in patients with a neurological disease, and amounts
to a mean of 82% (Guay et al. 2001). The treatment
success rate can be increased by repeated usage at-
tempts (McCullough et al. 2001).
Vardenafil and tadalafil demonstrate efficacy data
that can be presumed to be approximate to those of
sildenafil. Since near maximum inhibition of PDE-5
is already achieved with sildenafil (Turko et al. 1999),
an increase in efficacy is not to be expected with var-
denafil and tadalafil.
As yet, we need more data to assess the adverse ef-
fects of vardenafil and tadalafil, particularly in long-
term use and in high-risk groups.
Sildenafil has already been used in over 20 million
men in over 110 countries (Pfizer Inc. data on file)
and is one of the best studied pharmacological sub-
stances around. For example, 1095 scientific publica-
tions are available on Medline, the database of the
National Institute of Health, using the keyword sil-
denafil, 24 publications using vardenafil and 3 publi-
cations using tadalafil (as at August 25, 2002). Some 4
years after the market launch of sildenafil, the post-
marketing data show a high degree of concordance
with the efficacy and safety data obtained in the clini-
cal licensing studies (Sadovsky et al. 2001).
The Office of Drug Safety of the FDA (Federal
Drug Administration) collected and analyzed reports
of death in men prescribed sildenafil from its market-
ing in March 1998. In conclusion there did not ap-
pear to be an increase in death due to myocardial in-
farction above expected numbers in the same age
groups compared to sildenafil users (Wysowski DK
et al. 2002).
This adventage in terms of knowledge and safety
data makes sildenafil a safe and reliable treatment for
patients with erectile dysfunction.
Whether tadalafil or vadenafil are complementary
to sildenafil or not will be shown the years following
market introduction.
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Received: September 23, 2002 / Accepted: October 7, 2002
EUROPEAN JOURNAL OF MEDICAL RESEARCHOctober 29, 2002 445
Address for correspondance:
Professor Dr. med. Ursula Gresser
Praxisklinik Sauerlach
Internal Medicine
Tegernseer Landstr. 8
D-82054 Sauerlach, Germany
Phone: 0049-8104-88 78 22
Fax: 0049-8104-88 78 24
e-mail: info@praxisklinik-sauerlach.de
Professor Dr. med. Christoph Gleiter
Department of Clinical Pharmacology
University of Tübingen
Medizinische Klinik
Otfried-Müller-Str. 10
D-72076 Tübingen, Germany
Phone: 0049-7071-2978277
Fax: 0049-7071-295035
e-mail: christoph.gleiter@uni-tuebingen.de
EUROPEAN JOURNAL OF MEDICAL RESEARCH446 October 29, 2002
... The use of PAR in the rats model of ED has been well established Angulo et al., 2001;Tiwari, 2020;Yakubu & Jimoh, 2014). Interestingly, coadministration of PAR with Vardenafil, a phosphodiesterase-5 (PDE-5) inhibitor, has been reported to be effective (Angulo et al., 2003), but the side effects, including hypotension and retinitis pigmentosa most especially in patients with the underline diseases, defamed their use (Gresser & Gleiter, 2002). Therefore, there is a need for a continuous search of pharmacologically-active medicinal plants/ foods or their extracts that can combat ED, secondary to PAR administration with no side effects. ...
... Phosphodiesterase-5 (PDE-5) and cGMP are important biomolecules in male sexual function and the penile's erection process Oboh et al., 2017;Oyeleye et al., 2021). PDE-5′ catalyzes the breakdown of cGMP: an important molecule that facilitates muscle relaxation, increases blood flow, and consequently penile rigidity (Gresser & Gleiter, 2002). Hence, PDE-5 inhibition is required for adequate penile rigidity. ...
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... estimated to be 475 and 604 nM, respectively, which is beyond the observed exposure range but still within published data (Kitzen et al., 1988;Du et al., 2004). The potencies of dofetilide (QT) and sildenafil (TPR) were estimated to be 50.6 and 4.01 nM, respectively, which is within the observed exposure range and consistent with published data (Mounsey and DiMarco, 2000;Gresser and Gleiter, 2002). The g parameter was relatively low for all compounds and biomarker responses and particularly for dofetilide and QT effect, suggesting a shallow equilibrium concentrationbiomarker response relationship around its potency value (Table 5). ...
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