Review Article CURRENT STATUS AND FUTURE PROSPECTS OF PDE5

CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
Review Article
CURRENT STATUS AND FUTURE PROSPECTS OF PDE5
INHIBITORS FOR VARIOUS THERAPEUTIC IMPLICATIONS
Tanvi Dobhal*, Sukhpreet Kaur, Om Prakash Sharma, S.L.Hari Kumar
Rayat & Bahra Institute of Pharmacy. Sahauran, kharar, Distt-Mohali (Punjab), India
ABSTRACT
Phosphodiesterases are enzymes that catalyzes the hydrolysis of cAMP and /or cGMP
and thereby regulates intracellular levels of second messangers. Inhibition of PDEs leads
to increasing intracellular concentrations of endogenous cAMP/cGMP. Therefore,
inhibition of PDE can mediate a variety of physiological mechanisms at different cell and
organ levels. Phosphodiesterase type 5 (PDE5) hydrolyses cyclic guanylate
monophosphate (cGMP) specifically to 5' GMP. Strategies directed to promote inhibition
of PDE5 activity have been applied as therapeutic tools in neuronal and cardiovascular
conditions. The introduction of PDE5 inhibitors has revolutionised the treatment of
erectile dysfunction(ED) and their safety, efficacy and ease of administration has made
them the first line treatment for ED. This article reviews the current status and the future
trends of various PDE5 inhibitors in erectile dysfunction as well as in other non
erectogenic disorders.
Keywords: Phosphodiesterase, cAMP, cGMP , PDE5 Inhibitors.
INTRODUCTION
Phosphodiesterases (PDEs) are a
superfamily of enzymes that degrade
cyclic
adenosine
monophosphate
(cAMP)
and
cyclic
guanosine
monophosphate (cGMP) [1–3]. Eleven
cyclic PDE families with varying
selectivities for cAMP and/or cGMP
have been identified in mammalian
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tissues [4-8]) The cAMP specific
enzymes include PDE-4,7,8 ; cGMP
specific PDEs include PDE-5,6,9
whereas PDE-1,2,3,10 use both cGMP
and cAMP [8]. Therefore PDEs are
important
regulators
of
various
biochemical mechanisms mediated by
cAMP and/or cGMP.
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Table 1: PDE5 Inhibitors on tissue expression
PDE
ISOENZYME/
SUBSTRATE
Ca2+/calmodulin
Stimulated
TISSUE EXPRESSION
2
cGMP stimulated [12]
Adrenal gland, heart[13], lung,
liver, platelets [14]
3
cGMP-inhibited
cAMP-selective
4
cAMP-specific
Heart, lung, liver[15],
platelets,
Kidney,
T lymphocytes,
adipocytes, inflammatory cells
Sertoli cells, kidney, brain,
liver,
lung, inflammatory cells [1618]
5
cGMP-specific
platelets [19,20], Lung
[21,22], vascular
smooth muscle [23]
6
7
cGMP-specific
cAMP-specific,
high-affinity
8
cAMP-selective
9
cGMP-specific
10
cGMP-sensitive,
cAMP-selective
cGMP-sensitive,
dual specificity [35,36]
Photoreceptor [24]
Skeletal muscle, heart, kidney,
Brain, pancreas,
T lymphocytes [25]
Testes [26-29], eye, liver,
skeletal muscle,
Heart, kidney, ovary, brain,
T lymphocytes [30,31]
Kidney, liver, lung, brain
[32,33]
Testes, brain[34]
1
11
Heart, brain, lung, smooth
muscle,
T lymphocytes, sperm [9-11]
Skeletal muscle, prostate,
kidney,
liver, pituitary, testes and
salivary glands
PDE isoenzymes are present in nearly all
cells therefore inhibitors of these
isoenzymes have therapeutic actions in
14
SPECIFIC INHIBITORS
Volume 1 Issue 3 2012
KS505a, bepril,
Vinpocetine,
Flunarizine and
Amiodarone
EHNA, BAY 607550, Oxindole
and PDP
Cilostamide,
Enoxamone,
Milrinone,
Siguazodan
Rolipram,
Roflumilast,
Cilomilast,
Drotaverine,
Ibudilast
Sildenafil,
Vardenafil,
Tadalafil,
Zaprinast
Dipyridamole
BRL-50481,
BC30
PF-04957325
BAY 73-6691
None
None
various disorders such as dementia,
schizophrenia, depression, cardiac heart
failure, asthma, chronic obstructive
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pulmonary disease, multiple schlerosis,
chrohn's disease, erectile dysfunction in
men, persistent pulmonary hypertension
of the new born. Inhibition of cyclic
nucleotide PDEs allow cAMP/cGMP
concentrations to increase within cells
[37] and inhibition of PDE by PDE
inhibitors can cause a variety of cellular
effects and can influence various
physiological functions.
PDE5 is a cGMP specific PDE and is
mainly expressed in platelets, heart,
vascular smooth muscle, placenta,
skeletal muscles, pancreas and to much
lesser extent in brain, liver and lung.
Inhibitor of PDE5 isoenzymes have
therapeutic applications in various
diseases/ disorders.
ERECTILE DYSFUNCTION
Erectile dysfunction (ED) is defined by
the National Institutes of Health (NIH)
as the inability to achieve or maintain an
erection sufficient for satisfactory sexual
performance[38]. Penile erection is
caused through vascular pressure
changes within the corpora cavernosa
wherein the nitric oxide (NO)/cyclic
guanosine monophosphate (cGMP)
pathway plays the key physiological
mediator of erection. NO is released
during psychogenic, reflexogenic, or
nocturnal
tumescense,
to
cause
relaxation of the smooth muscle cells of
the trabeculae and arterioles of the
corpora cavernosa, thus increasing
penile blood flow and resulting in
erection. cGMP gets hydrolysed mainly
by the enzyme PDE5 thus causing
detumescense. PDE5 inhibitors compete
with cGMP for the enzyme, making
cGMP more available and prolonging
erection[39].
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Phosphodiesterase type 5 (PDE5)
inhibitors are the most efficient oral
drugs in the treatment of ED[40,41] and
should
be
considered
first-line
therapy.[42-44] Sildenafil has been
found to be effective and safe in cases of
ED
associated
with
diabetes
mellitus[44,45]
and
spinal
cord
injury[46]and in men with sexual
dysfunction secondary to antidepressant
therapy[47]. An open-label trial found
that patients preferred tadalafil and
vardenafil over sildenafil [48] yet most
evidence supports equal effectiveness
between sildenafil and vardenafil [49].
Udenafil is an oral PDE5 inhibitor for
the treatment of erectile dysfunction
(ED). In a multicenter, double-blind,
placebo-controlled phase III trial in men
with mild-to-severe ED, the drug
produced a significant improvement in
erectile function after 12 weeks of
treatment and was an effective and welltolerated therapy for ED of broadspectrum etiology and severity [50].
Udenafil is currently available in Korea,
Russia, Malaysia under the brand name
Zydena and in India under the brand
name Udzire but it is not yet approved in
US by US FDA. Avanafil is a highly
selective PDE5 inhibitor and has fast
onset of action for penile erection
compared with other PDE5 inhibitors. It
is known by the trademark name
Stendra. It demonstrates a favourable
and unique pharmacokinetic profile with
rapid onset of action and short t1/2
without accumulation of the drug and
has proven to be a safe and effective
medication in the treatment of ED
[51,52] .
Mirodenafil is a PDE5 inhibitor that has
been available in Korea since 2007 as
M-vix. A multicenter, randomized,
double-blind,
placebo
controlled,
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parallel-group, fixed-dose study was
conducted in Korea and showed the drug
to be effective and well tolerated in ED
due to several etiologies [53].
ALZHEIMER'S DISEASE
Alzheimer's disease (AD) is a common
age-related
mental
disorder
characterized by memory loss and
multiple cognitive impairments [54,55].
Alzheimer’s disease affects people in
different ways, but the most common
symptom pattern begins with gradually
worsening ability to remember new
information. This occurs because
disruption of brain cell function usually
begins in brain regions involved in
forming new memories. As damage
spreads, individuals experience other
difficulties such as memory loss that
disrupts daily life, challenges in planning
or
solving
problems,
difficulty
completing familiar tasks at home, at
work or at leisure, confusion with time
or place, trouble understanding visual
images and spatial relationships, new
problems with words in speaking or
writing, misplacing things and losing the
ability to retrace steps, decreased or poor
judgment, withdrawal from work or
social activities, changes in mood and
personality. Soluble guanylate cyclase
(sGC), a heterodimeric enzyme converts
guanosine triphosphate to cyclic
guanosine
monophosphate (cGMP).
This cGMP is a critical component of
NO-cGMP signaling pathway. cGMP is
hydrolysed
by
several
phosphodiesterases
sGC
5'-GTP
3',5'-cGMP
PDE
5'-GMP
16
cGMP is a second messenger nucleotide
that has been strongly implicated in the
process of learning and memory [56].
The cGMP-hydrolysing PDE2, PDE5,
and PDE9 and the cAMP-hydrolysing
PDE4 and PDE7 are located in the
hippocampus where they are likely to be
involved in memory and/or long-term
potentiation [57-59]. Hence PDE
inhibitors present a novel therapeutic
approach with which it is possible to
arrest cognitive decline or possibly
reverse the decline with cognition
enhancement [60,61]. PDE5 inhibitor
has been shown to enhance long term
memory retention in mice by modulating
mechanism involved in memory storage.
Moreover, the inhibition of PDE5
improves object memory [62,63] and
counteracts spatial learning impairment
induced by NOS inhibition [64,65] and
by blockade of cholinergic muscarinic
receptors in rats [64]. PDE5 inhibitors
are found to be active in rodent models
of Novel object recognition [66,67]. The
inhibiton of PDE5 by PDE5 inhibitors
also
attenuates
spatial
learning
impairment in the 14 unit T maze
induced by cholinergic blockade or by
inhibiting NO synthase or in aged rats
[64]. It has been shown that the PDE5
inhibitor sildenafil influences long-term
memory retention in mice by modulating
mechanisms involved in memory storage
(68).Other studies have shown that
sildenafil produces a dose-dependent
improvement of memory in mice tested
with elevated plus maze [69]. Vardenafil
also improved the memory performance
5'-GMP
of rats in Object recognition task ( ORT)
and was found to be more potent than
sildenafil. Although PDE5 inhibitors are
clinically available and are well tolerated
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a better understanding of the mechanism
underlying the effects of brain in
warranted to provide clinical context.
PULMONARY
HYPERTENSION
ARTERIAL
Pulmonary arterial hypertension (PAH)
is a progressive disease of pulmonary
arteries that is characterized by a
sustained increase in pulmonary pressure
and vascular remodeling [70]. Two
important pathological features of this
are decreased endothelial nitric oxide
production [71] and increased PDE5
expression and activity in pulmonary
artery smooth muscle cells [72-74] and
the right ventricular myocardium[75].
The rationale for the use of PDE5
inhibitors in PAH is augmentation of
cGMP pathway. PDE5 inhibitors inhibit
the hydrolysis of cGMP thereby increase
its levels with consequent vasodilatory,
anti-proliferative and pro-apoptotic
effects that may reverse pulmonary
arterial remodelling[74].
In PAH,
Ghofrani et al. [76] showed that daily
sildenafil intake improved exercise
capacity,
functional
class,
and
hemodynamics compared with placebo
maintained even after 1 year of therapy.
Ghofrani et al. [77] demonstrated in a
randomized controlled open-label trial
that oral sildenafil is a potent pulmonary
vasodilator acting synergistically with
inhaled iloprost in patients with severe
PAH or chronic thromboembolic. Sheth
et al. [78] showed that sildenafil
improved mean pulmonary artery
pressure, mean pulmonary capillary
wedge pressure, dyspnea score, and gas
transfer in severe secondary PH and
right ventricular dysfunction. The
phosphodiesterase type 5 inhibitor
sildenafil (Revatio) was approved for the
treatment
of
pulmonary
arterial
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hypertension by the Food and Drug
Administration (FDA) and by the
European Medicines Agency (EMEA) in
2005.
Affuso et al. [79] reported that in
idiopathic PAH, the quality of life and
exercise tolerance were improved
remarkably after a 6-month course of
tadalafil. Tadalafil (Adcirca) received
FDA approval for this indication in
2009.
Aizawa et al. [80] showed that long-term
oral vardenafil was a safe and effective
treatment for PH patients. Giacomini et
al. [81] indicated that vardenafil acted in
synergy with inhaled NO, permitted NO
reduction and discontinuation and
proved to be effective as a single, longterm treatment for PH. Vardenafil, has
not yet been approved for the treatment
of pulmonary arterial hypertension.
ENDOTHELIAL DYSFUNCTION
ED is now largely synonymous to
endothelial dysfunction, a known
precursor to atherosclerosis in terms of
molecular mechanisms and underlying
risk factors and it is known that men
with penile vascular dysfunction have
endothelial dysfunction in other vascular
beds. ED and generalized vascular
disease may be linked at the level of the
endothelium and a defective NO–cGMP
system plays a common characteristic in
these settings[82-84]. Numerous studies
suggest that PDE5 inhibitors might be
efficacious in reversing generalized
endothelial dysfunction. Acute sildenafil
treatment showed favourable effects on
brachial artery flow-mediated dilatation
up to 24 hours post-dose in men with
and without ED [29-31, 33,44] and in
patients with CAD [90] and chronic
heart failure [91]. Furthermore, chronic
treatment with sildenafil restores
endothelium-dependent relaxations at
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various sites of the vascular tree, even up
to 1 week after cessation of the treatment
[85,92,93,94] Chronic therapy also with
tadalafil led to a significant sustained
improvement of endothelial function in
patients with increased cardiovascular
risk regardless their degree of ED
[95,96-98]. Vardenafil restored impaired
endothelial function of cavernous and
brachial arteries[99,100] Endothelial
progenitor cells are thought to contribute
to endothelial and neovascular repair,
and their increased levels are associated
with lowered risk for cardiac death
[101]. ED patients, with or without
cardiovascular risk factors, exhibit
reduced endothelial progenitor cell
numbers. Tadalafil (chronically, in ED
patients with vascular risk factors) and
vardenafil (acutely, in healthy subjects
and ED patients) were associated with
increased numbers of circulating
endothelial progenitor cells, suggesting
an intriguing role of these drugs in the
mobilization and/or production of
endothelial progenitor cells that promote
endothelial rehabilitation [96,97,103].
BENIGN
PROSTATIC
HYPERPLASIA (BPH)
AND
LOWER
URINARY
TRACT
SYMPTOMS (LUTS)
BPH is a highly prevalent neoplasm in
ageing men and its clinical manifestation
LUTS is a major health concern for
ageing men [104] which considerably
impairs the quality of life of
patients,QoL [105,106]. One half of all
men with BPH are estimated to
experience LUTS [107] the most
common symptoms of which include
urinary hesitancy, weak stream and
nocturia [108-110]. Pharmacological
experiments have provided evidence that
NO is involved in regulating smooth
muscle tone in human prostate [111].
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PDE5 inhibitors
mediate
smooth
muscle relaxation not only in corpus
cavernosum, but also in the bladder
neck, urethra and prostate suggesting the
possible use of PDE5 inhibitors in the
treatment of LUTS secondary to BPH. In
an organ bath experiment carried by
Tinnel et al.[112] , PDE5 inhibitors were
found to significatly relax bladder,
prostate and urethral tissue and the rank
order of potency was Vardenafil >
Sildenafil > Tadalafil. Besides this, the
study also suggested that PDE5
inhibitors reduce the irritative symptoms
of BPH/LUTS in vivo. The first study to
demonstrate the clinical benefit of PDE5
inhibitors in BPH/LUTS was carried out
by Sairam et al.[113] where the effect of
sildenafil was assessed in LUTS in men
with ED and it was found that sildenafil
improved IPSS (International Prostate
Symptom Score) and QoL scores. The
effect of PDE5 inhibitors in BPH/LUTS
was later confirmed be a similar study
[114] where sildenafil (50mg) showed
positive effect on BPH/LUTS while
treating ED patients. In a study carried
out on 48 patients with ED and mild to
moderate LUTS, sildenafil showed
positive impact [115]. A multicentre,
randomised placebo controlled double
blind phase 2 trial suggested that
Tadalafil given once daily for LUTS
secondary to BPH improved IPSS and
QoL [116]. Also, Vardenafil is
considered a promising treatment option
for men with BPH/LUTS [117]. Studies
suggests that combination of PDE5
inhibitors and alpha blockers give
greater results in BPH/LUTS and ED
than did either drug alone [118-121] .
PRIAPISM
Priapism is defined as a persisting
painful and abnormal tumescence that
can occur without any sexual stimulation
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and which does not subside after sexual
intercourse or masturbation [122]. This
condition frequently results in erectile
failure and is considered a urologic
emergency [122,123] that requires
urgent treatment since the severity of the
long term consequences are in direct
proportion to the duration of the
priapism condition. Mechanism of
priapism
involves
PDE5
down
regulation in the penis resulting from the
altered signalling of the NO signalling
pathway [124]. Therefore PDE5 offers a
molecular target for the therapeutic
management of priapism suggesting the
use of PDE5 inhibitors as a preventive
strategy for the disorder [125]. In a
mouse model of recurrent priapism ,
treatment with PDE5 inhibitors reduced
priapism tendencies and regularised
PDE5 gene regulatory activity in the
penis [126]. PDE5 inhibitors have been
shown to alleviate recurrent priapism
when applied daily in a manner not
associated with stimulatory conditions
[127]. Burnett et al [128] reported their
experience for 7 patients with recurrent
priapism and noted that treatment with
sildenafil and tadalafil successfully
resolved
or
alleviated
priapism
recurrences in 6 of the 7 patients. PDE5
inhibitors for the treatment of recurrent
priapism remains investigational at
present and more work is needed to
establish optimal parameters for their
use in this context .
CYSTIC FIBROSIS
Great interest has been aroused by recent
basic research of PDE5 Inhibitors in the
treatment of cystic fibrosis.
Cystic
fibrosis (CF) is the most common life
threatening inheritable disease in
caucasians caused by mutation in the CF
transmembrane conductance regulator
(CFTR) gene [129,130] which encodes
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the main chloride channel expressed in
epithelia. CF disease causes abnormal
muco-ciliary clearance mainly in lungs
leading to a vicious cycle of
obstructive/infection/inflammation/that
progressively and reversibly damages
lungs tissue and architecture. Although
many organs are affected in CF,
pulmonary disease is the major cause of
morbidity and mortality [131,132]. To
test the hypothesis that PDE5 inhibitors
such as Sildenafil, Vardenafil and
Tadalafil when applied at therapeutic
doses are able to restore transepithelial
ion transport abnormalities of F508 delCFTR protein, experimental study was
conducted
in
CF
mice
[133]
homozygous for F508 del mutation
[134]. The F508 del-CFTR mouse model
was chosen because F508del is the most
common and most severe CF mutation
and because the mouse model
recapitulates at different levels the
human disease. Intraperitoneal injection
of PDE5 inhibitors at therapeutic doses t
oF508 del-CF mice interact with CFTR
propping open the mutant protein to
allow a normal flow of chloride ions
across the epithelium of nasal mucosa
thereby restoring the decreased or even
abolished CFTR dependent chloride
transport [135]. Also more recently
experimental studies conducted on
animals have shown that nebulizing
F508 del CF mice with PDE5 inhibitors
led to correction of the nasal chloride
transport [136]. Tadalafil gave largest
correction, sildenafil gave smallest but
highly significant correction. Single
inhaled therapeutic dose of Vardenafil
lasts atleast 8 hours. This clearly
suggests that inhalational route of PDE5
Inhibitors is potential therapy for CF.
Sildenafil was also found to reduce
neutrophil lung infiltration in murine
airways infected with P.aeruginosa
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placebo controlled, cross-referenced trial
designed to evaluate the efficacy of
sildenafil in RP and ischemic ulcers
[150].
Sildenafil causes vasodilation for less
than 60 minutes after intake and a dose
of 50mg three or four times a day leads
to improved blood flow in patients with
secondary RP [151,152,153] . Tadalafil
has a longer half life of 17.5 hours as
compared to sildenafil having a half life
of 3.8 hours and is regarded to be an
alternative for those patients with RP
who did not improve with sildenafil
[154].
[137]. Antoniu [138] supported the
theory that sildenafil and vardenafil are
promising agents for CF therapy. In
toxicological studies it was shown that
pre treatment with sildenafil attenuates
acrolein-triggered airway inflammation
which is associated with overproduction
[139].
RAYNAUD'S PHENOMENON
Raynaud's phenomenon is described as
transient digital ischemic vasospasm
that occurs upon exposure to cold
temperature or emotional distress
leading to pale and cyanotic skin with
post ischemic phase of hyperemia ; the
archetypal
"tricolore phenomenon"
[140]. Maurice Raynaud in 1862 first
described the disease as a "local
asphyxia of the extremities" and later
Thomas Lewis divided the Raynaud's
disease into primary Raynaud's disease
and secondary Raynaud's phenomenon
[140,141]. Primary Raynaud's disease is
common with mild symptoms and
complications do not arise unless there is
a permanent injury [142] whereas in
secondary Raynaud's phenomenon (RP)
the episodes are intense and painful
[143,144] and occurs in patients with
connective tissue disease [144] and also
upto 90% patients with systemic
sclerosis have secondary RP [145]. The
aim of the treatment in patients with RP
is to improve the digital blood flow and
to prevent digital ischemia. NO is potent
vasodilator and its effect is mediated via
cyclic
guanosine
monophosphate
(cGMP). PDE rapidly degrade cGMP in
vivo [146] . Sildenafil and Tadalafil are
specific inhibitors of PDE5 isoenzyme
and have been evaluated for their effect
in RP in open studies with a small
number of patients where they have been
found to improve it [147-149] and this
was confirmed in the only double blind,
20
CONCLUSION
PDE5 Inhibitors are amongst the most
promising class of drugs for the
treatment of erectile dysfunction. Their
unique mechanism of action and
pleiotropic pharmacologic properties
have generated a focus for basic and
clinical research with PDE5 inhibitors as
novel and therapeutic options for the
treatment and management of several
other chronic diseases. Although
substantial evidence and an absolute
assessment of risk benefit ratio is
required for accepting PDE5 inhibitors
for new indications.
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