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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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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-
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
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
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-
October 29, 2002
Eur J Med Res (2002) 7: 435-446
I. Holzapfel Publishers 2002
U. Gresser
, C. H. Gleiter
Praxisklinik Sauerlach, Internal Medicine, Germany,
Department of Clinical Pharmacology, University of Tübingen, Germany
2.1. P
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).
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.
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-
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).
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%.
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-
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.
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.
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.
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).
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-
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
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.
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
Interesting long-term data for repeated use exist on
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.
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
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
values (concentration at which the
enzyme activity is 50% inhibited) of sildenafil (Table
The reason for this is that IC
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-
Table 1. Distribution and function of phosphodiesterases (Francis et al. 2001, Osterloh 2001)
PDE isoenzyme/ Tissue distribution Possible functional significance of PDE
PDE 1 / Brain, heart, skeletal muscles, Vascular muscular weakness, taste,
cGMP liver, vascular muscles, visceral muscles olfaction
PDE 2 / Adrenal cortex, corpus cavernosum, heart, Olfaction, adrenocorticosteroid
cGMP visceral muscles, brain, skeletal muscles production
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
PDE 7 / Skeletal muscles, heart, lymphocytes T-cell activation; skeletal muscles;
cAMP metabolism
PDE 8 / Widespread; e.g. testes, ovaries, bowel T-cell activation
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
PDE 11 / Skeletal muscles, heart, vascular muscles ?
cGMP and visceral muscles (corpus cavernosum,
cAMP prostate), pituitary gland, testes, liver and
ment results, depending on the study conditions se-
This lack of measurement precision concerns all
PDE-5 inhibitors. The IC
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
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-
Sildenafil Vardenafil
cGMP Tadalafil
Fig. 1. Chemical structure of
cGMP and the PDE-5 inhibitors
sildenafil, vardenafil and tadala-
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
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
Table 2. IC
P values of sildenafil according to analyses by
various laboratories.
Laboratory IC
50 of
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
Vardenafil IC
Tadalafil IC
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).
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.
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).
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
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.
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-
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).
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-
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
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
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
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-
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.
As knowledge stands at present, PDE-5 inhibitors are
the method of choice for the treatment of erectile
dysfunction, alongside treatment for the underlying
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-
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
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
Professor Dr. med. Christoph Gleiter
Department of Clinical Pharmacology
University of Tübingen
Medizinische Klinik
Otfried-Müller-Str. 10
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... 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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This study focused on the effect of unripe (UPP) and ripe (RPP) plantain peels' extracts (200 and 400 mg/kg) on sexual behavior, hormonal profiles [testosterone, follicle‐stimulating hormone (FSH), and luteinizing hormone (LH)], and enzymes [acetylcholinesterase (AChE), phosphodiesterase‐5′ (PDE‐5), arginase, angiotensin‐I converting enzyme (ACE), ecto‐5′neucleotidase, and adenosine deaminase (ADA)] in paroxetine (PAR)‐induced penile dysfunction rats. From the result, arginase, PDE‐5′, ACE, ecto‐5′‐nucleotidase ADA, and AChE activities, sexual activities, hormonal profile, and NO level were reduced, while thiobarbituric acid reactive species (TBARS) level increased (p < .05) relative to normal control rats. However, treatment with UPP and URP reduced the activities of these enzymes, decreased TBARS levels, and increased hormones, and penile NO levels in PAR‐induced rats. Thus, the use of UPP and RPP could be channeled towards the improvement of sexual performance in erectile dysfunction (ED) disorder. Practical applications Plantain fruits are a tropical staple food crop commonly consumed at various stages of ripeness and cooking methods. However, its peels are regarded as a waste product with reported cases of environmental menace. Interestingly, plantain peel is being used as a major raw material for industrial applications in the agro‐based industries and in folklore for the treatment of many human ailments due to its rich phytochemicals such as polyphenols, carotenoids, alkaloids, etc., which have been reported. A prelude study has also indicated its usefulness in ED management, but further pharmacological investigations are needed to proffer information on its effect in ED management and its anti‐androgenic activity in male Wistar rats. The information from this study could be of pharmaceutical importance in designing natural remedies capable of improving penile rigidity, hormone profiles, and alteration of enzymes linked with ED.
... This value falls inside the defined threshold for a compound to be considered a BBB-crossing agent. More importantly, the pharmacokinetic assessments revealed that tadalafil reached considerable concentrations in the mice brain (0.84-1.82 µM) following a single oral dose (15 mg/kg), which is sufficient to inhibit PDE5 in the CNS [123,129,130]. Another study conducted In vitro Synergistic inhibition of cell growth [190] Exisulind + Docetaxel In vitro In vivo ...
Since the discovery of phosphodiesterase-5 (PDE5) enzyme overexpression in the central nervous system (CNS) malignancies, investigations have explored the potential capacity of current PDE5 inhibitor drugs for repositioning in the treatment of brain tumors, notably glioblastoma multiforme (GBM). It has now been recognized that these drugs increase brain tumors permeability and enhance standard chemotherapeutics effectiveness. More importantly, studies have highlighted the promising antitumor functions of PDE5 inhibitors, e.g., triggering apoptosis, suppressing tumor cell growth and invasion, and reversing tumor microenvironment (TME) immunosuppression in the brain. However, contradictory reports have suggested a pro-oncogenic role for neuronal cyclic guanosine monophosphate (cGMP), indicating the beneficial function of PDE5 in the brain of GBM patients. Unfortunately, due to the inconsistent preclinical findings, only a few clinical trials are evaluating the therapeutic value of PDE5 inhibitors in GBM treatment. Accordingly, additional studies should be conducted to shed light on the precise effect of PDE5 inhibitors in GBM biology regarding the existing molecular heterogeneities among individuals. Here, we highlighted and discussed the previously investigated mechanisms underlying the impacts of PDE5 inhibitors in cancers, focusing on GBM to provide an overview of current knowledge necessary for future studies.
... 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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Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h-1, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were IC 50 = 475 (11), IC 50 = 4.01 (5.4), EC 50 = 50.6 (93), and IC 50 = 47.8 (16), and efficacies (%RSE within parentheses) were I max = 0.944 (1.7), Imax = 1.00 (1.3), E max = 0.195 (9.9), and Imax = 0.745 (4.6) for ivabradine, sildenafil, dofetilide, and pimobendan. Hill parameters were estimated with good precision and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach integrating data from different studies and compounds for refined preclinical safety margin assessment. SIGNIFICANCE STATEMENT: A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure, and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), wherein system- (turnover rates) and drug-specific parameters (e.g., potencies and efficacies) were sought. The model-predicted equilibrium concentration-biomarker response relationships and was used for safety assessment (predictions of 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval.
... ст., ЛСС -на 234 дин × сек × см -5 . Это согласуется с результатами исследования SUPER-1, в котором лечение силденафилом (20, 40, 80 мг 3 раза в сутки) по сравнению с плацебо приводило к улучшению ключевых показателей гемодинамики уже к 12-й неделе наблюдения [5,6,[9][10][11]. Снижение ДЛАср в среднем составило: в группе 60 мг -2,1 мм рт. ...
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Over the last decade, the interest in the treatment of idiopathic pulmonary hypertension (IPAH) has greatly increased because of the development and implementation of innovative therapeutic approaches. One of the modern drug groups for the treatment of pulmonary arterial hypertension are phosphodiesterase type 5 inhibitors (PDE5), which can cause pulmonary vasodilation via a NO-dependent mechanism.The aim of the research was to study the efficacy and safety of sildenafil treatment in patients with IPAH received 16-week course and to study sildenafil impact on clinical, hemodynamic and functional status.Material and methods: 20 patients with IPAH (mean age 40.9±11.5 years) functional class (FC) II-IV (WHO), who were receiving standard therapy (anticoagulants, diuretics, glycosides, calcium antagonists), were prescribed sildenafil 20 mg three times a day for 16 weeks. Initially, and after 16 weeks of treatment we studied FC, and the results of the six-minute walk test (6MWT), transthoracic echocardiography (ECHO), right heart catheterization (RHC) and laboratory tests to determine the safety of the therapy were carried out, as well.Results: the group of patients had 6MWT distance of 344±116 m at the beginning of the study. For about 90% of the patients suffered from dizziness, 75% - from the pain in the heart, 65% of the patients had edema and 35% - hepatomegaly. The patients suffered from severe pulmonary hypertension according to the functional and hemodynamic status. The estimated pulmonary artery systolic pressure (PASP) according to ECHO results was 89.6±22 mm Hg. According to the data from RHC we noted the elevation of mean pulmonary arterial pressure (mPAP) to 56.3±19 mm Hg, of pulmonary vascular resistance (PVR) to 1218±709 dyne/sec x per x cm-5 and the decrease in cardiac output (CO) - 3.4±0.8 l/min/m2.There were slight increasing in 6MWT distance (+23 m, p>0.05) and a statistically significant improvement in clinical status in comparison with the initial data: dizziness - 71%, heart pain - 38%, edema and hepatomegaly were observed in 15% and 14% (p
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Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although many studies have been conducted to improve the prognosis of FGR in infants, no effective intrau-terine treatment method has been established. In this study, we aimed to use tadalafil, a phos-phodiesterase 5 (PDE5) inhibitor, as a novel intrauterine treatment, and conducted several basic and clinical studies. This study also aimed to clarify the effects of tadalafil on placental mTOR signaling. Tadalafil was administered to mice with L-NG-nitroarginine methyl ester (L-NAME)-induced FGR and associated preeclampsia (PE). Placental phosphorylated mTOR (p-mTOR) signaling was assessed by fluorescent immunohistochemical staining and Western blotting. The expression of p-mTOR was significantly decreased in mice with FGR at 13 days postcoitum (d.p.c.) but it recovered to the same level as that of the control at 17 d.p.c. following tadalafil treatment. The results were similar for 4E-BP-1 and S6R proteins, which act downstream in the mTOR signaling pathway. We demonstrated that the tadalafil treatment of FGR in mice improved placental mTOR signaling to facilitate fetal growth. Our study provides the key mechanistic detail about the mode of action of tadalafil and, thus, would be helpful for future clinical studies.
Tadalafil is an effective, reversible, and competitive phosphodiesterase 5 inhibitor mainly used to treat erectile dysfunction. This study investigated the bioequivalence of generic and marketed formulations of 10‐mg tadalafil tablets under fasted and fed conditions. This open‐label, randomized, single‐dose, 2‐period crossover study included 53 healthy Chinese men (aged 20‐43 years). Plasma samples were collected from 0.5 hours before treatment to 72 hours after each dose and analyzed using ultra‐high‐performance liquid chromatography coupled with tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety assessments were performed throughout the study. For the fasted state, the 90% confidence intervals of the geometric mean ratios between the generic and marketed formulations were 86.1% to 99.1% for the maximum plasma concentration and 88.4% to 100.3% for the area under the plasma concentration–time curve from time 0 to infinity, and the corresponding values under the fed state were and 99.9% to 108.4% and 95.7% to 104.3%, respectively. All data were within the accepted bioequivalence range of 80% to 125%. After consuming high‐fat, high‐calorie meals in the fed condition, the time to the maximum plasma concentration was similar between the formulations, and area under the plasma concentration–time curve from time 0 to infinity and maximum plasma concentration were 10.2% and 6.55% higher, respectively, for the marketed formulation. Thus, food had no clinically relevant effect on tadalafil exposure following a single oral dose in healthy Chinese men. No serious adverse reactions were reported. These results indicated that the analyzed generic and marketed tadalafil tablets were bioequivalent with similar safety profiles.
With an increase in the detection of structural and functional analogues of phosphodiesterase type 5 inhibitors (PDE-5i) in dietary supplements (DS) and foods, public health is threatened. Some products advertise natural ingredients despite containing PDE-5i that can cause serious adverse effects on human health. To avoid detection during routine screening, novel PDE-5i have been synthesised and added to DS and foods. The purpose of this study was to detect, identify, and quantify 94 PDE-5i and related compounds in DS and foods. Furthermore, the study investigated the detection cases and compared them by sample type, formulation, and compounds. The HPLC and LC-MS/MS methods were validated for limit of detection (LOD), limit of quantification (LOQ), linearity, and recovery in solid and liquid type samples. Both HPLC and LC-MS/MS showed satisfactory results, which were in conformance with the ICH guidelines. A total of 404 samples, including DS (99), and foods (305) were purchased from online and offline markets. Samples divided into 5 types of formulation were analysed; tablet, capsule, pilula (herbal medicine pill), powder and liquid type. Of these 130 samples (47 of 99 DS, and 83 of 305 foods) contained one or more PDE-5i or related compounds. Among the five types of formulation, the tablet type showed the highest detection rate (61.1%) in DS, whereas the capsule type showed the highest detection rate (53.8%) in food samples. This study will be helpful for monitoring illegal ED-related products, providing information to consumers, and ultimately contributing to protecting public health.
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Diabetes Miletus (DM) is a global epidemic disease. It is estimated that there are already 415 million adults aged 20–79 years diabetics worldwide. Sildenafil citrate is a phosphodiesterase type 5 (PDE5) inhibitor, which increases cyclic guanosine monophosphate (cGMP) and metformin (MET) is a biguanide used for the treatment of type 2 diabetes which increases peripheral insulin sensitivity. Aim: This study aims to assess the effect of sildenafil citrate and metformin on lipid profile and glycemic control in diabetic and prediabetic albino rats. Materials and methods: Adult male albino rats are used and divided into nine groups each group consists of 10 rats, diabetes is induced by feeding a high-fat diet (HFD) for an initial period of 2 weeks followed by a single intraperitoneal injection of (35 mg/kg) Streptozotocin. Prediabetes is induced by feeding (HFD) and glucose in water for a period of 2 weeks. Sildenafil was given in a dose of (5 &10 mg/kg/day orally for 4 weeks), metformin was given in a dose of (50 &100 mg/kg/day orally for 4 weeks) using oral gavages to normal healthy rats, diabetic and prediabetic rats. Blood samples were collected after 4 weeks of treatment in all experimental groups. Results: Combined administration of sildenafil and metformin on diabetic rats improving hyperglycemia, oxidative stress, and hyperlipidemia induced by streptozotocin than the administration of metformin or sildenafil alone. Conclusion: Sildenafil has beneficial effects against some diabetic complications. The present study showed that sildenafil with metformin has beneficial effects against diabetic complications.
This develops the topic of Ageing in better health. Here we return to the biology of ageing, that was first introduced in Chap. 1, but with a special emphasis on brain plasticity, a very important topic that is the focus of a fast-developing research program, and we also review psychological health in old age. Initially mentally healthy persons may be at risk of experiencing serious deterioration of their mental capacities as they age; therefore, we devote a section in this chapter to review mental pathologies in the elderly. Special emphasis is given to the analysis of the various forms of dementia, including Alzheimer’s disease. From there we proceed to address those aspects of ageing that affect sexual behaviour. The challenges experienced by people with a disability (mental or physical) who are becoming older are also the topic of a section in this chapter. We conclude the chapter with a section devoted to older people who reach very advanced ages: the centenarians, semi-supercentenarians, and supercentenarians.
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Nitrogen-containing heterocycles represent a major source of pharmacological probes and drug candidates. To extend their molecular diversity and their potential biological activities, it is of importance to design and synthesize new N-heterocyclic scaffolds. Therefore, aza-diketopiperazines (aza-DKPs), the aza analogues of well-known 2,5-diketopiperazines (DKPs), emerged as a promising new scaffold. Although the first synthesis of an aza-DKP dates from 1951, significant developments have been made during the last decade. This feature article summarizes the different synthetic strategies to access and functionalise aza-DKPs. Their biological properties and potential applications in medicinal chemistry and drug discovery are discussed as well.
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Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) >/=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.
Introduction: The present study assessed the efficacy and safety of oral doses of sildenafil. taken as required (not more than once daily), during a 1-year period, in men with erectile dysfunction (ED). Patients and methods: Two previous double-blind, placebocontrolled studies recruited 584 patients with ED of no known organic cause; 519 of these patients elected to receive open-label sildenafil for 1 year. However, only 500 patients (mean age 54 years, range 19-71) were randomized to receive treatment. All patients started at a dose of 25 mg, with an option to reduce the dose to 10 mg or increase it to 50 mg and then 100 mg, based on toleration and efficacy; where clinically indicated, an intermediate dose of 75 mg was also permitted. Patients were withdrawn from treatment if they derived no benefit from sildenafil or if safety concerns arose. Results: A total of 441 (88%) patients completed the 1-year study. 59 (12%) withdrew; only 13 (2.6%) patients were withdrawn through lack of efficacy. Of 17 (3.4%) patients withdrawn due to adverse events, in only five (1 %) patients were the adverse events ascribed to sildenafil; 29 patients withdrew for other causes. The most frequently reported adverse events were flushing, dyspepsia and headache. Of 35 serious adverse events reported, none was attributed to sildenafil. Conclusion: In men with ED of no known organic cause, oral sildenafil is effective and well tolerated during long-term treatment.
To date, relative cellular levels of cGMP and cGMP-binding proteins have not been considered important in the regulation of smooth muscle or any other tissue. In rabbit penile corpus cavernosum, intracellular cGMP was determined to be 18 ± 4 nm, whereas the cGMP-binding sites of types Iα and Iβ cGMP-dependent protein kinase (PKG) and cGMP-binding cGMP-specific phosphodiesterase (PDE5) were 58 ± 14 nm and 188 ± 6 nm, respectively, as estimated by two different methods for each protein. Thus, total cGMP-binding sites (246 nm) greatly exceed total cGMP. Given this excess of cGMP-binding sites and the high affinities of PKG and PDE5 for cGMP, it is likely that a large portion of intracellular cGMP is associated with these proteins, which could provide a dynamic reservoir for cGMP. Phosphorylation of PDE5 by PKG is known to increase the affinity of PDE5 allosteric sites for cGMP, suggesting the potential for regulation of a reservoir of cGMP bound to this protein. Enhanced binding of cGMP by phosphorylated PDE5 could reduce the amount of cGMP available for activation of PKG, contributing to feedback inhibition of smooth muscle relaxation or other processes. This introduces a new concept for cyclic nucleotide signaling.