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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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Volume 1 Issue 3 2012
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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CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
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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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CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
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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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Volume 1 Issue 3 2012
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.
REFERENCES
1.
2.
3.
4.
Volume 1 Issue 3 2012
Beavo JA. Cyclic nucleotide phosphodiesterases:
functional implications of multiple isoforms.
Physiol. Rev. 1995;75: 725–748
Soderling SH and Beavo JA. Regulation of
cAMP
and
cGMP
signaling:
new
phosphodiesterases and new functions. Curr.
Opin. Cell Biol. 2000;12: 174–179
Corbin JD and Francis SH. Cyclic GMP
phosphodiesterase-5: target of sildenafil. J. Biol.
Chem.1999; 274: 13729–13732
Cheung
WY.
Cyclic
nucleotide
phosphodiesterase.
Adv
Biochemical
Psychopharmacol.1970;3: 51-65.
www.earthjournals.org
CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Conti M. Phosphodiesterases and cyclic
nucleotide signaling in endocrine cells. Mol
Endocrinol. 2000;14: 1317-1327.
Soderling SH, Beavo JA. Regulation of cAMP
and cGMP signaling: new
phosphodiesterases
and new functions. Curr Opin Cell Biol.
2000;12: 174-179
Francis SH, Turko IV, Corbin JD. Cyclic
nucleotide phosphodiesterases: relating structure
and function. Prog Nucleic Acid Res Mol Biol.
2001;65: 1-52.
Mehats C, Andersen CB, Filopanti M, Jin SL,
Conti M. Cyclic nucleotide phosphodiesterases
and their role in endocrine cell signaling. Trends
Endocrinol Metabol 2002; 13: 29-35.
Yan C, Zhao AZ, Bentley JK, Loughney K,
Ferguson K, Beavo JA . Molecular cloning and
characterization of a calmodulin-dependent
phosphodiesterase enriched in olfactory sensory
neurons. Proc Natl Acad Sci USA. 1995;92:
9677-9681.
Loughney K, Martins TJ, Harris EA, Sadhu K,
Hicks JB, Sonnenburg WK, Beavo JA,
Ferguson K. Isolation and characterization of
cDNAs
corresponding
to
two
human
calcium,
calmodulin-regulated,
3',5'-cyclic
nucleotide
phosphodiesterases.
J
Biol
Chem.1996;271: 796-806.
Yu SM, Hung LM, Lin CC. cGMP-elevating
agents suppress proliferation of
vascular
smooth muscle cells by inhibiting the activation
of epidermal growth factor
signaling
pathway. Circulation. 1997; 95: 1269-1277.
Rosman GJ, Martins TJ, Sonnenburg WK,
Beavo JA, Ferguson K, Loughney K.
Isolation and characterization of human cDNAs
encoding a cGMP-stimulated 3',5'-cyclic
nucleotide phosphodiesterase. Gene. 1997;191:
89-95.
Rivet-Bastide M, Vandecasteele G, Hatem S,
Verde I, Benardeau A, Mercadier JJ,
Fischmeister R. cGMP-stimulated cyclic
nucleotide phosphodiesterase regulates the
basal calcium current in human atrial myocytes.
J Clin Invest. 1997;99: 2710- 2718.
Sadhu K, Hensley K, Florio VA, Wolda SL.
Differential expression of the cyclic
GMPstimulated phosphodiesterase PDE2A in human
venous and capillary endothelial cells. J
Histochem Cytochem.1999;47: 895-906.
Palmer D, Maurice DH. Dual expression and
differential regulation of phosphodiesterase 3A
and phosphodiesterase 3B in human vascular
smooth
muscle:
implications
for
phosphodiesterase 3 inhibition in human
21
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Volume 1 Issue 3 2012
cardiovascular tissues. Mol Pharmacol. 2000; 58:
247-252.
Tenor H, Hatzelmann A, Kupferschmidt R,
Stanciu L, Djukanovic R, Schudt C, Wendel A,
Church MK, Shute JK. Cyclic nucleotide
phosphodiesterase isoenzyme activities in human
alveolar macrophages. Clin Exp Allergy. 1995;
25: 625-633.
Tenor H, Hatzelmann A, Wendel A, Schudt C.
Identification of phosphodiesterase IV activity
and its cyclic adenosine monophosphatedependent up-regulation in a human keratinocyte
cell line (HaCaT). J Invest Dermatol. 1995; 105:
70-74.
Tenor H, Staniciu L, Schudt C, Hatzelmann A,
Wendel A, Djukanovic R, Church MK, Shute
JK. Cyclic nucleotide phosphodiesterases from
purified human CD4+ and CD8+ T lymphocytes.
Clin Exp Allergy.1995; 25: 616-624.
Hamet P, Coquil JF. Cyclic GMP binding and
cyclic GMP phosphodiesterase in rat platelets. J
Cyclic Nucleotide Res. 1978; 4: 281-290.
Coquil JF, Franks DJ, Wells JN, Dupuis M,
Hamet P. Characteristics of a new binding
protein distinct from the kinase for guanosine
3':5'-monophosphate in rat platelets. Biochim
Biophys Acta. 1980; 631: 148-165.
[21] Francis SH, Corbin JD. Purification of
cGMP-binding protein phosphodiesterase from
rat lung. Meth Enzymol.1988; 159: 722-729.
Francis SH, Lincoln TM, Corbin JD.
Characterization of a novel cGMP binding
protein from rat lung. J Biol Chem. 1980; 255:
620-626.
Sebkhi A, Strange JW, Phillips SC, Wharton J,
Wilkins MR. Phosphodiesterase type 5 as a
target for the treatment of hypoxia-induced
pulmonary hypertension. Circulation. 2003; 107:
3230-3235.
Zhang X, Feng Q, Cote RH. Efficacy and
selectivity of phosphodiesterase targeted drugs in
inhibiting
photoreceptor
phosphodiesterase
(PDE6) in retinal photoreceptors. Invest
Ophthalmol Vis Sci. 2005; 46: 3060-3066.
Smith SJ, Brookes-Fazakerley S, Donnelly LE,
Barnes PJ, Barnette MS, Giembycz MA.
Ubiquitous expression of phosphodiesterase 7A
in human proinflammatory and immune cells.
Am J Physiol. 2003; 284:L279-289.
Wang P, Wu P, Egan RW, Billah MM. Human
phosphodiesterase 8A splice variants: cloning,
gene organization, and tissue distribution. Gene.
2001; 280:183-194.
Hayashi M, Kita K, Ohashi Y, Aihara E,
Takeuchi K. Phosphodiesterase isozymes
www.earthjournals.org
CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
involved in regulation of HCO3- secretion in
isolated mouse duodenum in vitro. Biochem
Pharmacol. 2007;74: 1507-1513.
Kobayashi T, Gamanuma M, Sasaki T,
Yamashita Y, Yuasa K, Kotera J, Omori K.
Molecular comparison of rat cyclic nucleotide
phosphodiesterase 8 family: unique expression
of PDE8B in rat brain. Gene. 2003; 319: 21-31.
Perez-Torres S, Cortes R, Tolnay M, Probst A,
Palacios JM, Mengod G. Alterations on
phosphodiesterase type 7 and 8 isozyme mRNA
expression in Alzheimer's disease brains
examined by in situ hybridization. Exp
Neurol.2003; 182: 322-334.
Glavas NA, Ostenson C, Schaefer JB, Vasta V,
Beavo JA. T cell activation upregulates cyclic
nucleotide phosphodiesterases 8A1 and 7A3.
Proc Natl Acad Sci USA. 2001; 98: 6319-6324.
Dong H, Osmanova V, Epstein PM, Brocke S.
Phosphodiesterase
8
(PDE8)
regulates
chemotaxis of activated lymphocytes. Biochem
Biophys Res Commun. 2006; 345: 713-719.
Soderling SH, Bayuga SJ, Beavo JA. Cloning
and characterization of a cAMPspecific cyclic
nucleotide phosphodiesterase. Proc Natl Acad
Sci USA. 1998; 95: 8991-8996.
Soderling SH, Bayuga SJ, Beavo JA.
Identification and characterization of a novel
family of cyclic nucleotide phosphodiesterases. J
Biol Chem. 1998; 273: 15553-15558.
Loughney K, Snyder PB, Uher L, Rosman GJ,
Ferguson K, Florio VA. Isolation and
characterization of PDE10A, a novel human 3',
5'-cyclic nucleotide phosphodiesterase. Gene
.1999 ; 234: 109-117.
Fawcett L, Baxendale R, Stacey P, McGrouther
C, Harrow I, Soderling S, Hetman J, Beavo JA,
Phillips
SC.
Molecular
cloning
and
characterization
of
a
distinct
human
phosphodiesterase gene family: PDE11A. Proc
Natl Acad Sci USA. 2000. 97: 3702-3707.
Weeks JL 2nd, Zoraghi R, Francis SH, Corbin
JD. N-Terminal domain of phosphodiesterase11A4 (PDE11A4) decreases affinity of the
catalytic site for substrates and tadalafil, and is
involved in oligomerization. Biochemistr.
2007;46: 10353-10364.
Bender AT and Beavo JA. Cyclic nucleotide
phosphodiesterases: molecular regulation to
clinical use. Pharmacol.Rev. 2006; 58, 488–520.
Impotence.
NIH
Consens
Statement.
1992;10(4):1-33.
Dean RC, Lue TF. Physiology of penile erection
and pathophysiology of erectile dysfunction.
Urol Clin North Am. 2005;32(4): 379–395.
22
40. Erectile Dysfunction Guideline Update Panel.
The management of erectile dysfunction: an
update. Baltimore, Md.: American Urological
Association Education and Research,
Inc.;
2005.
41. Carson CC, Lue TF. Phosphodiesterase type 5
inhibitors for erectile dysfunction. BJU Int.
2005;96(3): 257-280.
42. Montague DK, Jarow JP, Broderick GA, et al.,
for the Erectile Dysfunction Guideline Update
Panel. Chapter 1: The management of erectile
dysfunction: an AUA update. J Urol.
2005;174(1): 230-239
43. Esposito K, Giugliano F, Di Palo C, et al. Effect
of lifestyle changes on erectile dysfunction in
obese men: a randomized controlled trial.
JAMA. 2004;291(24): 2978- 2984.
44. Vardi M, Nini A. Phosphodiesterase inhibitors
for erectile dysfunction in patients with diabetes
mellitus. Cochrane Database Syst Rev. 2007;(1):
CD002187.
45. Rendell MS, Rajfer J, Wicker PA, Smith MD;
Sildenafil Diabetes Study Group. Sildenafil for
treatment of erectile dysfunction in men with
diabetes: a randomized controlled trial. JAMA.
1999;281(5): 421-426.
46. Derry FA, Dinsmore WW, Fraser M, et al.
Efficacy and safety of oral sildenafil (Viagra) in
men with erectile dysfunction caused by spinal
cord injury. Neurology. 1998;51(6): 1629-1633.
47. Nurnberg HG, Hensley PL, Gelenberg AJ, Fava
M, Lauriello J, Paine S. Treatment of
antidepressant-associated sexual dysfunction
with sildenafil: a randomized controlled trial.
JAMA. 2003;289(1): 56-64.
48. Tolrà JR, Campaña JM, Ciutat LF, Miranda EF.
Prospective, randomized, open-label, fixed-dose,
crossover study to establish preference of
patients with erectile dysfunction after taking the
three PDE-5 inhibitors. J Sex Med. 2006;3(5):
901-909.
49. Rubio-Aurioles E, Porst H, Eardley I, Goldstein
I, for the Vardenafil-Sildenafil Comparator
Study Group. Comparing vardenafil and
sildenafil in the treatment of men with erectile
dysfunction and risk factors for cardiovascular
disease: a randomized, double-blind, pooled
crossover study. J Sex Med. 2006;3(6): 10371049.
50. Paick J-S, Kim SW, Yang DY, Kim JJ, Lee SW,
Ahn TY, Choi HK, Suh J-K, and Kim SC. The
efficacy and safety of udenafil, a new selective
phosphodiesterase type 5 inhibitor, in patients
with erectile dysfunction. J Sex Med. 2008;5:
946–953.
Volume 1 Issue 3 2012
www.earthjournals.org
CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
51. Kotera J, Mochida H, Inoue H, Noto T, Fujishige
K, Sasaki T, Kobayashi T, Kojima K,Yee S,
Yamada Y, Kikkawa K and Omori K. Avanafil,
a
Potent
and
Highly
Selective
Phosphodiesterase-5 Inhibitor for Erectile
Dysfunction. The Journal Of Urology. 2012;188:
668-674.
52. Alwaal A, Al-Mannie R, Carrier S. Future
prospects in the treatment of erectile
dysfunction: focus on avanafil. Drug Design,
Development and Therapy. 2011;5: 435–443.
53. Paick JS, Ahn TY, Choi HK, et al. Efficacy and
safety
of
mirodenafil,
a
new
oral
phosphodiesterase type 5 inhibitor, for treatment
of erectile dysfunction. J Sex Med. 2008;5(11):
2672–2680.
54. Mattson MP. Pathways Towards and Away from
Alzheimer’s Disease. Nature. 2004; 430(7000):
631–639.
55. Selkoe DJ. Alzheimer’s Disease: Genes,
Proteins, and Therapy. Physiological Reviews.
2001;81(2): 741-766.
56. Prickaerts J, Sik A, Staay F J, Blokland A.
Dissociable effects of acetylcholinesterase
inhibitors and phosphodiesterase type 5
inhibitors on object recognition memory:
acquisition
versus
consolidation.
Psychopharmacolog. 2005;177: 81-390.
57. Miro X, Torres P, Palacios JM, Mengod G.
Differential distribution of cAMP-specific
phosphodiesterase 7A mRNA in rat brain and
peripheral organs. pubmed. 2001;40: 201- 204.
58. Rutten K, Smits L, Lieben C. and Blokland A.
The PDE4 inhibitor rolipram reverses object
memory impairment induced by acute tryptophan
depletion in the rat.
Psycopharmacology.
2007;192: 275–282
59. Gong B, Vitolo O, Trinchese F,
Liu S,
Shelanski M
and Arancio O. Persistent
improvement in synaptic and cognitive functions
in an Alzheimer mouse model after rolipram
treatment. The journal of clinical investigation.
2004;114: 1624-1634.
60. Bales KR, Plath N, Svenstrup N and Menniti FS.
Phosphodiesterase Inhibition to Target the
Synaptic Dysfunction in Alzheimer’s Disease.
Top Med Chem. 2010; 6: 57–90.
61. Rutten K , Basile JL, Prickaerts J, Blokland A
and Vivian JA. Selective PDE inhibitors
rolipram and sildenafil improve object retrieval
performance in adult cynomolgus macaques.
Psychopharmacology. 2008;196: 643–648.
62. Prickaerts J, Van Staveren WCG, Sik A, Ittersum
MMV, Niewohner U, Van Der Staay FJ,
Blokland A sand De VenteJ. Effects Of Two
23
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
Volume 1 Issue 3 2012
Selective Phosphodiesterase Type 5 Inhibitors,
Sildenafil And Vardenafil, On Object
Recognition Memory And Hippocampal Cyclic
GMP Levels In The Rat. Neuroscience.
2002;113(2): 351-361
Rutten K, Vente J, Sik A, Ittersum M, Prickaerts
J and Blokland A. The selective PDE5 inhibitor,
sildenafil, improves object memory in Swiss
mice and increases cGMP levels in hippocampal
slice. Behavioral Brain Research. 2005;164; 1–
16.
Devan BD, Duffy KB, Bowker JL, Bharati IS,
Nelson CM, Daffin Jr. LW, Spangler EL and
Ingram DK. Phosphodiesterase type 5 (PDE5)
inhibition and cognitive enhancement. Drugs of
the Future. 2005;30(7): 1-12.
Devan BD., Bowker J, Duffy K, Bharati I,
Jimenez M, Mercado D, Nelson C, Spangler E.
and Ingram D. Phosphodiesterase inhibition by
sildenafil citrate attenuates a maze learning
impairment in rats induced by nitric oxide
synthase inhibition.
Psychopharmacology.
2006; 183: 439–445.
Prickaerts J, Sik A, Van Staveren WCG,
Koopmans G, Steinbusch HWM, Van der Staay
FJ, Vente JD. Blokland A. Phosphodiesterase
type 5 inhibition improves early memory
consolidation
of
object
information.
Neurochemistry International. 2004;45: 915–
928.
Rutten K, Prickaerts J, Hendrix M, Van der
Staay J, Sik A, Blokland A. Time-dependent
involvement of cAMP and cGMP in
consolidation of object memory: Studies using
selective phosphodiesterase type 2, 4 and 5
inhibitors. European Journal of Pharmacology.
2007;558: 107–112.
Baratti CM and Boccia MM. Effects of sildenafil
on long-term retention of an inhibitory avoidance
response
in
mice.
Behavioural
Pharmacology .1999;10(8): 731-737.
Singh M and Parle M. Sildenafil improves
acquisition and retention of memory in mice.
Indian Journal Of Pharmacology. 2003;47: 318324.
Runo JR, Loyd JE. Primary pulmonary
hypertension. Lancet. 2003;361: 1533–1544.
Giaid A, Saleh D. Reduced expression of
endothelial nitric oxide synthase in thelungs of
patients with pulmonary hypertension. N Engl J
Med. 1995;333: 214-21.
Black SM, Sanchez LS, Mata-Greenwood E,
Bekker JM, Steinhorn RH, Fineman JR. sGC and
PDE5 are elevated in lambs with increased
pulmonary blood flow and pulmonary
www.earthjournals.org
CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
hypertension. Am J Physiol Lung Cell Mol
Physiol. 2001;281: L1051-L1057.
Murray F, MacLean MR, Pyne NJ. Increased
expression of the cGMP-inhibited cAMPspecific (PDE3) and cGMP binding cGMPspecific (PDE5) phosphodiesterases in models of
pulmonary hypertension. Br J Pharmacol.
2002;137:1187-94.
Wharton J, Strange JW, Moller GM, et al.
Antiproliferative effects of phosphodiesterase
type 5 inhibition in human pulmonary artery
cells. Am J Respir Crit Care Med. 2005;172:
105-113.
Nagendran J, Archer SL, Soliman D, et al.
Phosphodiesterase type 5 is highly expressed in
the hypertrophied human right ventricle, and
acute inhibition of phosphodiesterase type 5
improves contractility. Circulation. 2007;116:
238-48.
Ghofrani HA, Osterloh IH, Grimminger F. Case
history: Sildenafil: From angina to erectile
dysfunction to pulmonary hypertension and
beyond. Nat Rev Drug Discov. 2006;5: 689–702.
Ghofrani HA, Wiedemann R, Rose F,
Olschewski H, Schermuly RT, Weissmann N,
Seeger W, Grimminger F. Combination therapy
with oral sildenafil and inhaled iloprost for
severe pulmonary hypertension. Ann Intern Med.
2002;136: 515–22.
Sheth A, Park JE, Ong YE, Ho TB, Madden BP.
Early haemodynamic benefit of sildenafil in
patients with coexisting chronic thromboembolic
pulmonary hypertension and left ventricular
dysfunction. Vascul Pharmacol. 2005;42: 41–5.
Affuso F, Palmieri EA, Di Conza P, Guardasole
V, Fazio S. Tadalafil improves quality of life and
exercise tolerance in idiopathic pulmonary
arterial hypertension. Int J Cardiol. 2006;108:
429–31.
Aizawa K, Hanaoka T, Kasai H, Kogashi K,
Kumazaki S, Koyama J, Tsutsui H, Yazaki Y,
Watanabe N, Kinoshita O, Ikeda U. Long-term
vardenafil therapy improves hemodynamics in
patients with pulmonary hypertension. Hypertens
Res. 2006;29: 123– 128.
Giacomini M, Borotto E, Bosotti L, Denkewitz
T, Reali-Forster C, Carlucci P, Centanni S,
Mantero A, Iapichino G. Vardenafil and weaning
from inhaled nitric oxide: effect on pulmonary
hypertension in ARDS. Anaesth Intensive Care.
2007;35: 91–3.
Kirby M, Jackson G, Simonsen U. Endothelial
dysfunction links erectile dysfunction to heart
disease. Int J Clin Pract. 2005;59: 225–9.
24
83. Vlachopoulos C, Aznaouridis K, Ioakeimidis N,
Rokkas K, Tsekoura D, Vasiliadou C, Stefanadi
E, Askitis A, Stefanadis C. Arterial function and
intima-media thickness in hypertensive patients
with erectile dysfunction. J Hypertens. 2008;26:
1829–36.
84. Agrawal V, Ellins E, Donald A, Minhas S,
Halcox J, Ralph DJ. Systemic vascular
endothelial dysfunction in Peyronie’s disease. J
Sex Med 2008 [Epub ahead of print].
85. Desouza C, Parulkar A, Lumpkin D, Akers D,
Fonseca VA. Acute and prolonged effects of
sildenafil on brachial artery flow-mediated
dilatation in type 2 diabetes. Diabetes Care.
2002;25: 1336–9.
86. Kimura M, Higashi Y, Hara K, Noma K, Sasaki
S, Nakagawa K, Goto C, Oshima T, Yoshizumi
M, Chayama K. PDE5 inhibitor sildenafil citrate
augments endothelium-dependent vasodilation in
smokers. Hypertension. 2003;41: 1106–10.
87. Vlachopoulos C, Tsekoura D, Alexopoulos N,
Panagiotakos D, Aznaouridis K, Stefanadis C.
Type 5 Phosphodiesterase inhibition by
sildenafil abrogates acute smoking-induced
endothelial dysfunction. Am J Hypertens.
2004;17: 1040–4.
88. Gori T, Sicuro S, Dragoni S, Donati G, Forconi
S, Parker JD. Sildenafil prevents endothelial
dysfunction induced by ischemia and reperfusion
via opening of adenosine triphosphate-sensitive
potassium channels: A human in vivo study.
Circulation. 2005;111: 742–6.
89. Attinà TM, Malatino LS, Maxwell SR, Padfield
PL,Webb DJ. Phosphodiesterase type 5
inhibition reverses impaired forearm exerciseinduced vasodilatation in hypertensive patients. J
Hypertens. 2008;26: 501–7.
90. Halcox JP, Nour KR, Zalos G, Mincemoyer RA,
Waclawiw M, Rivera CE, Willie G, Ellahham S,
Quyyumi AA. The effect of sildenafil on human
vascular function, platelet activation, and
myocardial ischemia. J Am Coll Cardiol.
2002;40: 1232– 42.
91. Katz SD, Balidemaj K, Homma S,Wu H,Wang J,
Maybaum S. Acute type 5 phosphodiesterase
inhibition with sildenafil enhances low-mediated
vasodilation in
patients with chronic heart
failure. J Am Coll Cardiol. 2000;36: 845–51.
92. Guazzi M, Samaja M, Arena R, Vicenzi M,
Guazzi MD. Long-term use of sildenafil in the
therapeutic management of heart failure. J Am
Coll Cardiol. 2007;50: 2136–44.
93. Aversa A, Vitale C, Volterrani M, Fabbri A,
Spera G, Fini M, Rosano GM. Chronic
administration of sildenafil improves markers of
Volume 1 Issue 3 2012
www.earthjournals.org
CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
endothelial function in men with type 2 diabetes.
Diabet Med. 2008; 25: 37–44.
94. Behr-Roussel D, Oudot A, Caisey S, Coz OL,
Gorny D, Bernabé J, Wayman C, Alexandre L,
Giuliano FA. Daily treatment with sildenafil
reverses endothelial dysfunction and oxidative
stress in an animal model of insulin resistance.
Eur Urol. 2008;53: 1272–81.
95. Rosano GM, Aversa A, Vitale C, Fabbri A, Fini
M, Spera G. Chronic treatment with tadalafil
improves endothelial function in men with
increased cardiovascular risk. Eur Urol. 2005;47:
214–22.
96. Foresta C, Ferlin A, De Toni L, Lana A, Vinanzi
C, Galan A, Caretta N. Circulating endothelial
progenitor cells and endothelial function after
chronic tadalafil treatment in subjects with
erectile dysfunction. Int J Impot Res. 2006;18:
484–8.
97. Bocchio M, Pelliccione F, Passaquale G,
Mihalca R, Necozione S, Desideri G, Francavilla
F, Ferri C, Francavilla S. Inhibition of
phosphodiesterase type 5 with tadalafil
is
associated to an improved activity of circulating
angiogenic cells in men withcardiovascular risk
factors and erectile dysfunction. Atherosclerosis.
2008;196: 313–9.
98. Aversa A, Greco E, Bruzziches R, Pili M,
Rosano G, Spera G. Relationship between
chronic
tadalafil
administration
and
improvement of endothelial function in men with
erectile dysfunction: A pilot study. Int J Impot
Res. 2007;19: 200–7.
99. Mazo E, Gamidov S, Iremashvili V. The effect
of vardenafil on endothelial function of brachial
and cavernous arteries. Int J Impot Res. 2006;18:
464–9.
100. Komori K, Tsujimura A, Takao T, Matsuoka Y,
Miyagawa Y, Takada S, Nonomura N, Okuyama
A. Nitric oxide synthesis leads to vascular
endothelial growth factor synthesis via the
NO/cyclic
guanosine
3′,5′-monophosphate
(cGMP) pathway in human corpus cavernosal
smooth muscle cells. J Sex Med. 2008;5: 1623–
35.
101. Hill JM, Zalos G, Halcox JP, Schenke WH,
Waclawiw MA, Quyyumi AA, Finkel T.
Circulating endothelial progenitor cells, vascular
function, and cardiovascular risk. N Engl J Med.
2003;348: 593–600.
102. Foresta C, Ferlin A, De Toni L, Lana A, Vinanzi
C, Galan A, Caretta N. Circulating endothelial
progenitor cells and endothelial function after
chronic tadalafil treatment in subjects with
25
erectile dysfunction. Int J Impot Res. 2006;18:
484–8.
103. Foresta C, Caretta N, Lana A, De Toni L,
Biagioli A, Vinanzi C, Ferlin A. Relationship
between vascular damage degrees and
endothelial progenitor cells in patients with
erectile dysfunction: Effect of vardenafil
administration and PDE5 expression in the bone
marrow. Eur Urol. 2007;51: 1411–7.
104. Nickel JC. The overlapping lower urinary tract
symptoms of benign prostatic hyperplasia and
prostatitis. Curr Opin Urol. 2006;16: 5-10.
105. Guess HA. Epidemiology and natural history of
benign prostatic hyperplasia. Urol Clin North
Am. 1995; 22: 247–61.
106. Carbone DJ Jr, Hodges S. Medical therapy for
benign prostatic hyperplasia: sexual dysfunction
and impact on quality of life. Int J Impot Res.
2003;15: 299–306.
107. AUA Practice Guideline Committee. AUA
guideline on management of benign prostatic
hyperplasia
(2003).
http://www.auanet.org/content/guidelines-andquality-care/clinical-guidelines. cfm? sub =bph.
Accessed October 16, 2008.
108. Edwards JL. Diagnosis and management of
benign prostatic hyperplasia. Am Fam Physician.
2008;77: 1403-10.
109. Neal DE, Neal RR, Donovan J. Benign Prostatic
Hyperplasia. In: Health Care Needs Assessment:
The Epidemiologically Based Needs Assessment
Reviews. Edited by Stevens A, Raftery J, Mant J,
Simpson S. Abington: Radcliffe Publishing,
chapt. 12, 2004: 91-158.
110. Levy A, Samraj GP. Benign prostatic
hyperplasia: when to 'watch and wait,' when and
how to treat. Cleve Clin J Med. 2007;74(Suppl
3): S15-20.
111. Takeda M, Tang R, Shapiro E, et al. Effects of
nitric oxide on human and canine prostates.
Urology. 1995;45: 440–446.
112. Tinel H, Ludwig BS, Hütter J and Sandner P.
Pre-clinical evidence for the use of
phosphodiesterase-5 inhibitors for treating
benign prostatic hyperplasia and lower urinary
tract symptoms. BJU International. 2006:98;
1259 –1263.
113. Sairam K, Kulinskaya E, McNicholas TA, et al.
Sildenafil influences lower urinary
tract
symptoms. BJU Int. 2002; 90: 836–839.
114. Ying J, Yao D, Jiang Y, et al. The positive effect
of sildenafil on LUTS from BPHwhile treating
ED. Zhonghua Nan Ke Xue. 2004;10: 681–683.
115. Mulhall JP, Guhring P, Parker M, Hopps C.
Assessment of the impact of sildenafil citrate on
Volume 1 Issue 3 2012
www.earthjournals.org
CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
lower urinary tract symptoms in men with
erectile dysfunction. J Sex Med. 2006; 3: 662–
667.
116. McVary KT, Roehrborn CG, Kaminetsky JC, et
al. Tadalafil relieves lower urinary tract
symptoms secondary to benign prostatic
hyperplasia. J Urol. 2007;177: 1401– 1407.
117. Stief CG, Porst H, Neuser D, et al. A
randomised, placebo-controlled study to assess
the efficacy of twice-daily vardenafil in the
treatment of lower urinary tract symptoms
secondary to benign prostatic hyperplasia. Eur
Urol. 2008;53: 1236–1244.
118. Kaplan SA, Gonzalez RR, Te AE. Combination
of alfuzosin and sildenafil issuperior to
monotherapy in treating lower urinary tract
symptoms and erectile dysfunction. Eur Urol.
2007;51: 1717–1723.
119. Bechara A, Romano S, Casabe A, et al.
Comparative efficacy assessment of tamsulosin
vs. tamsulosin plus tadalafil in the treatment of
LUTS/BPH. Pilot study. J Sex Med. 2008; 5:
2170–2178.
120. Liguori G, Trombetta C, De Giorgi G, et al.
Efficacy and safety of combined oral therapy
with tadalafil and alfuzosin: an integrated
approach to the management of patients with
lower urinary tract symptoms and erectile
dysfunction. Preliminary report. J Sex Med.
2009; 6: 544–552.
121. Chung BH, Lee JY, Lee SH, et al. Safety and
efficacy of the simultaneous administration of
udenafil and an alpha-blocker in men with
erectile dysfunction
concomitant with
BPH/LUTS. Int J Impot Res. 2009;21: 122–128.
122. Hauri D, Spycher M, Bruhlmann W: Erection
and priapism- a new pathophysiological concept.
Urol Int.1983; 88: 138-45.
123. Hashmat AI, Rehman JU: Priapism. In: Hashmat
AI, Das S (eds.), The Penis. Philadelphia, Lea &
Febiger.1993; pp 219-43.
124. Champion HC, Bivalacqua TJ, Takimoto E, Kass
DA, and Burnett AL. Phosphodiesterase-5A
dysregulation in penile erectile tissue is a
mechanism of priapism. PNAS. 2005; 102(5):
1661–1666.
125. Burnett
AL, Bivalacqua
TJ, Champion
HC, Musicki
B.
Long-term
oral
phosphodiesterase 5 inhibitor therapy alleviates
recurrent priapism. Urology. 2006; 67(5): 10431048.
126. Bivalacqua TJ, Champion HC, Mason W,
Burnett AL. Long-term phosphodiesterase type 5
inhibitor therapy reduces priapic activity in
26
transgenic sickle cell mice. J Urol. 2006;175:
387.
127. Burnett AL, Bivalacqua TJ, Champion HC,
Musicki B. Long-term phosphodiesterase 5
inhibitor therapy alleviates recurrent priapism.
Urology. 2006;67: 104–8.
128. Burnett AL, Bivalacqua TJ, Champion HC, et al.
Feasibility of the use of phosphodiesterase type 5
inhibitors in a pharmacologic prevention
program for recurrent priapism. J Sex Med.
2006;3: 1077–84.
129. Kerem B, Rommens JM, Buchanan JA,
Markiewicz D, Cox TK, Chakravarti A,
Buchwald M, Tsui LC. Identification of the
cystic fibrosis gene: genetic analysis. Science.
1989;245: 1073–1080.
130. Riordan JR, Rommens JM, Kerem B, Alon N,
Rozmahel R, Grzelczak Z, Zielenski J, Lok S,
Plavsic N, Chou JL, et al. Identification of the
cystic fibrosis gene: cloning and characterization
of complementary DNA. Science. 1989;245:
1066–1073.
131. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis.
N Engl J Med. 2005;352: 1992-2001.
132. Davis PB. Cystic fibrosis since 1938. Am J
Respir Crit Care Med. 2006;173: 475-482.
133. Lubamba B ,Lecourt H, Lebacq J, Lebecque P,
DeJonge H, Wallemacq P and Leal T. Preclinical
evidence that sildenafil and vardenafil activate
chloride transport in cystic fibrosis. Am.J.
Respir.Crit.CareMed. 2008;177: 506–515.
134. Van Doorninck JH, French PJ, Ver-beek E,
Peters RH, Morreau H, Bijman J and Scholte BJ.
A mouse model for the cystic fibrosis delta f508
mutation. EMBO J. 1995; 14: 4403–4411.
135. Lubamba B, Lecourt H, Lebacq J, Lebecque P,
DeJongeH , Wallemacq P and Leal T. Preclinical
evidence that sildenafil and vardenafil activate
chloride transport in cystic fibrosis. Am.J.
Respir.Crit.CareMed. 2008; 177: 506–515.
136. Lubamba B, Lebacq J, Reychler G, Marbaix
E,Wallemac P, Lebecque P, and Leal T. Inhaled
phosphodiesterase type 5 inhibitors restore
chloride transport in cystic fibrosis mice.
Eur.Respir.J. 2011;37: 72–78.
137. Poschet JF, Timmins GS, Taylor-Cousar JL,
Ornatowski W, Fazio J, Perkett E,Wilson KR,Yu
HD,
deJonge
HR
and
Deretic
V.
Pharmacological modulation of cGMP levels by
phosphodiesterase5 inhibitors as a therapeutic
strategy for treatment of respiratory pathology in
cystic fibrosis. Am.J. Physiol. Lung Cell Mol.
Physiol. 2007;293: L712-719.
Volume 1 Issue 3 2012
www.earthjournals.org
CRITICAL REVIEW IN PHARMACEUTICAL SCIENCES
ISSN 2319-1082
138. Antoniu SA. PDE5 inhibitors for cystic fibrosis:
Can they also enhance chloride transport? Expert
Opin Investig Drugs. 2008;17: 965–8.
139. Wang T, Liu Y, Chen L, Wang X, Hu XR, Feng
YL, Liu DS, Xu D ,Duan YP ,Lin J, Ou XM and
Wen FQ. Effect of sildenafil on acrolein induced
airway inflammation and mucus production in
rats. Eur.Respir.J. 2009; 33: 1122–1132.
140. Raynaud M. Local Asphyxia and Symmetrical
Gangrene of the Extremities. London: New
Sydenham Society. 1862.
141. Lewis T. Experiments relating to the peripheral
mechanisms involved in spasmodic arrest of the
circulation in the fingers, a variety of Raynaud’s
disease. Heart. 1929;15: 7–101.
142. LeRoy EC, Medsger TA Jr. Raynaud’s
phenomenon: a proposal for classification. Clin
Exp Rheumatol. 1992;10(5): 485–488.
143. Wigley FM. Raynaud’s phenomenon. N Engl J
Med. 2002;347: 1001–1008.
144. Bakst R, Merola JE, Franks AG Jr, Sanchez M.
Raynaud’s phenomenon: pathogenesis and
management. J Am Acad Dermatol. 2008;59:
633–653.
145. Rosenkranz S, Diet F, Karasch T, Weibrauch J,
Wassermann K, Erdmann E. Sildenafil improved
pulmonary hypertension and peripheral blood
flow in a patient with scleroderma-associated
lung fibrosis and the Raynaud phenomenon
[letter]. Ann Intern Med. 2003;139: 871–872.
146. Barst RJ. A review of pulmonary arterial
hypertension: role of ambrisentan. Vasc Health
Risk Manag. 2007;3(1): 11–22
147. Simonneau G, Burgess G, Parpia T, Badesch D.
Sildenafil improves exercise ability and
hemodynamics in patients with pulmonary
arterial hyper-tension associated with connective
tissue disease. Ann Rheum Dis. 2005;64 Suppl
111:109.
148. Rosenkranz S, Diet F, Karasch T, Weinbrauc J,
Wasserman K, Erdman E. Sildenafil improved
pulmonary hypertension and peripheral blood
flow in patient with scleroderma-associated lung
fibrosis and Raynaud phenomenon. Ann Int
Med. 2003;139: 871-2.
149. Gore J, Silver R. Oral sildenafil for the treatment
of Raynaud’s phenomenon and digital ulcers
secondary to systemic sclerosis. Ann Rheum Dis.
2005;64: 1387.
150. Freedman RR, Girgis R, Mayes MD. Acute
effect of nitric oxide on Raynaud’s phenomenon
in scleroderma. Lancet. 1999;354: 739.
151. Kamata Y, Kamimura T, Iwamoto M, Minota S.
Comparable effects of sildenafil citrate and
alprostadil on severe Raynaud’s phenomenon in
27
a patient with systemic sclerosis. Clin Exp
Dermatol. 2005;30: 451.
152. Kumana CR, Cheung GTY, Lau CS. Severe
digital ischaemia treated with phosphodiesterase
inhibitors. Ann Rheum Dis. 2004;63: 1522–
1524.
153. Rosenkranz S, Diet F, Karasch T et al. Sildenafil
improved
pulmonary
hypertension
and
peripheral blood Xow in a patient with
scleroderma-associated lung Wbrosis and
Raynaud’s phenomenon. Ann Int Med.
2003;139(10): 871–873.
154. Baumhaekel M, ScheZer P, Boehm M. Use of
tadalafil in patient with secondary Raynaud’s
phenomenon not responding to sildenafil.
Microvasc Res 2005; 69: 178–179.
Volume 1 Issue 3 2012
www.earthjournals.org