|
Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 30, 2009
Contents
Phosphodiesterase-5 Inhibitors and
their Use in the Treatment of Urological Conditions
Executive Editor: Perimenis Petros
Editorial: Pp. 3463
[PMID:
19860691 PubMed - indexed for MEDLINE]
PDE5 Inhibitors: In Vitro and In Vivo
Pharmacological Profile Pp. 3464-3475
D. Kouvelas, A. Goulas, G. Papazisis, C. Sardeli and
C. Pourzitaki
[Abstract] [Purchase
Article] [PMID:
19860692 PubMed - indexed for MEDLINE]
Phosphodiesterase Type 5 Inhibitors: Unmet Needs
Pp. 3476-3485
K. Hatzimouratidis and D. G. Hatzichristou
[Abstract] [Purchase
Article]
[PMID:
19860693 PubMed - indexed for MEDLINE]
Phosphodiesterase Type 5 Inhibitors for the Management
of Erectile Dysfunction: Preference and Adherence to Treatment
Pp. 3486-3495
T. F. Al-Shaiji and G. B. Brock
[Abstract] [Purchase
Article]
[PMID:
19860694 PubMed - indexed for MEDLINE]
Prophylaxis of Erectile Function After Radical Prostatectomy
with Phosphodiesterase Type 5 Inhibitors Pp. 3496-3501
F. Deho, A. Gallina, A. Salonia, A. Briganti, N. Suardi,
G. Zanni, G. Guazzoni, P. Rigatti and F. Montorsi
[Abstract] [Purchase
Article]
[PMID:
19860695 PubMed - indexed for MEDLINE]
PDE5 Inhibitors in the Treatment of LUTS Pp.
3502-3505
M. J. Speakman
[Abstract] [Purchase
Article]
[PMID:
19860696 PubMed - indexed for MEDLINE]
Is There a Role for PDE5 Inhibitors in the Management
of Male Infertility Due to Defects in Testicular or Epididymal
Function? Pp. 3506-3520
F. Dimitriadis, P. Tsounapi, M. Saito, T. Watanabe, A.
Sylakos, S. Tsabalas, I. Miyagawa and N. Sofikitis
[Abstract] [Purchase
Article] [PMID:
19860697 PubMed - indexed for MEDLINE]
PDE5 Inhibitors in Non-Urological Conditions
Pp. 3521-3539
C. Vlachopoulos, D. Terentes-Printzios, N. Ioakeimidis,
K. Rokkas and C. Stefanadis
[Abstract] [Purchase
Article] [PMID:
19860698 PubMed - indexed for MEDLINE]
Phosphodiesterase-5 Inhibitors: Future Perspectives
Pp. 3540-3551
Giannitsas Konstantinos and Perimenis Petros
[Abstract] [Purchase
Article]
[PMID:
19860699 PubMed - indexed for MEDLINE]
General Articles
Recent Advances of Fluorescent Technologies for Drug
Discovery and Development Pp. 3552-3570
Chiranjib Chakraborty, Chi-Hsin Hsu, Zhi-Hong Wen and
Chan-Shing Lin
[Abstract] [Purchase
Article]
[PMID:
19860700 PubMed - indexed for MEDLINE]
Role of Calcitonin Gene-Related Peptide in Gastric
Mucosal Defence and Healing Pp. 3571-3576
S. Evangelista
[Abstract] [Purchase
Article]
[PMID:
19860701 PubMed - indexed for MEDLINE]
Fibroblast Growth Factor-2 Antagonist and Antiangiogenic
Activity of Long-Pentraxin 3-Derived Pp. 3577-3589
Synthetic Peptides D. Leali, P. Alessi, D. Coltrini, M.
Rusnati, L. Zetta and M. Presta
[Abstract]
[Purchase
Article]
[PMID:
19860702 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[PMID:
19860691 PubMed - indexed for MEDLINE]
Editorial: Phosphodiesterase-5 Inhibitors
and their Use in the Treatment of Urological Conditions
The introduction of orally administered phosphodiesterase-5
inhibitors into clinical practice 10 years ago has been a
revolution in the field of urology. The availability of a
convenient to use, safe -despite initial concerns- and effective
treatment for erectile dysfunction of varying severity and
etiology, has radically changed the way that physicians, but
most importantly patients, approach this condition. Most of
the expectations raised have been fulfilled, and more than
10 years of experience and research with sildenafil, vardenafil
and tadalafil has increased our understating of erectile dysfunction
pathophysiology, its psychosocial correlates and factors associated
with treatment success or failure. Despite this, efforts to
satisfy unmet needs are ongoing: new PDE-5 inhibitors are
being developed and novel formulations of existing ones, like
once-a-day tadalafil, have already enter the pharmaceutical
market. Now that treatment options are more than ever before
patient preference and adherence issues have become important
and the focus of significant amount of research.
PDE-5 inhibitors have been successfully used not only for
correcting erectile dysfunction but also to preserve erectile
function in men treated with radical prostatectomy for prostate
cancer. In this setting PDE-5 inhibitors have been shown to
be a useful adjunct to improved surgical nerve-sparing techniques.
Research is ongoing, aiming to establish the optimal treatment
regimen for penile rehabilitation.
Evidence is accumulating suggesting that PDE-5 inhibitors
may be used in the future by urologists not only for ED treatment
but management of BPH- related lower urinary tract symptoms,
premature ejaculation, priapism and male infertility.
PDE-5 inhibitors are mainly used in urology but the approval
of sildenafil for the treatment of pulmonary hypertension
a few years ago renewed interest in cardiovascular applications,
the field where this drug class was originally studied. The
role of PDE-5 inhibitors in the management of heart failure,
hypertension, and ischemic heart disease is being actively
investigated with promising results.
This edition is aiming to summarize current knowledge regarding
use of PDE-5 inhibitors in their primary indication, erectile
dysfunction, but also to discuss the potential of expansion
of their use in other urological and important non-urological
indications as suggested by numerous preclinical and clinical
studies.
References
[1] Kouvelas D, Goulas A, Papazisis G, Sardeli C, Pourzitaki
C. PDE5 inhibitors: in vitro and in vivo
pharmacological profile. Curr Pharm Des 2009; 30: 3464-3475.
[2] Hatzimouratidis K, Hatzichristou DG. Phosphodiesterase
type 5 inhibitors: Unmet needs. Curr Pharm Des 2009; 30: 3476-3485.
[3] Al-Shaiji TF, Brock GB. Phosphodiesterase type 5 inhibitors
for the management of erectile dysfunction: Preference and
adherence to treatment. Curr Pharm Des 2009; 30: 3486-3495.
[4] Deho F, Gallina A, Salonia A, Briganti A, Suardi N, Zanni
G, et al. Prophylaxis of erectile function after
radical prostatectomy with phosphodiesterase type 5 inhibitors.
Curr Pharm Des 2009; 30: 3496-3501.
[5] Speakman MJ. PDE5 inhibitors in the treatment of LUTS.
Curr Pharm Des 2009; 30: 3502-3505.
[6] Dimitriadis F, Tsounapi P, Saito M, Watanabe T, Sylakos
A, Tsabalas S, et al. Is there a role for PDE5 inhibitors
in the management of male infertility due to defects in testicular
or epididymal function? Curr Pharm Des 2009; 30: 3506-3520.
[7] Vlachopoulos C, Terentes-Printzios D, Ioakeimidis N, Rokkas
K, Stefanadis C. PDE5 inhibitors in non-urological conditions.
Curr Pharm Des 2009; 30: 3521-3539.
[8] Giannitsas K, Perimenis P. Phosphodiesterase-5 inhibitors:
future perspectives. Curr Pharm Des 2009; 30: 3540-3551.
Perimenis Petros
University Hospital of Patras,
Urology Dept, Building A,
4th floor, Patras, 26500,
Greece
E-Mail: petperim@upatras.gr
[Back to top]
[Purchase
Article] [PMID:
19860692 PubMed - indexed for MEDLINE]
PDE5 Inhibitors: In Vitro and In Vivo Pharmacological
Profile
D. Kouvelas, A. Goulas, G. Papazisis, C. Sardeli and
C. Pourzitaki
PDE5 inhibitors have been clearly established as first-line
therapy for the treatment of erectile dysfunction (ED). Three
PDE5 inhibitors −
sildenafil (Viagra®),
vardenafil (Levitra®)
and tadalafil (Cialis®)
- are currently approved by the FDA and the EMEA for use in
ED, whereas sildenafil is also marketed under a different
proprietary name (Revatio®)
for the treatment of pulmonary arterial hypertension (PAH).
A forth PDE5 inhibitor, udenafil (Zydena®),
is currently marketed. In the present review the molecular
basis and the mechanism of action of PDE5 inhibitors is discussed.
In addition experimental and clinical data concerning their
effects on different tissues, organs and systems is systematically
reviewed and their possible beneficial action in numerous
disorders is presented.
[Back to top]
[Purchase
Article] [PMID:
19860693 PubMed - indexed for MEDLINE]
Phosphodiesterase Type 5 Inhibitors: Unmet Needs
K. Hatzimouratidis and D. G. Hatzichristou
Erectile dysfunction (ED) has been revolutionized during the
last two decades, as several treatment options are available
today.Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil,
tadalafil, vardenafil) are currently the first choice treatment
option for ED by most physicians and patients due to their
high efficacy rates and favourable safety profiles. Despite
the fact that more than 50 million ED patients have been treated
successfully worldwide with PDE5i several issues remain to
be addressed. Patients with severe neurologic damage, diabetes
mellitus, or severe vascular disease may be resistant to PDE5i.
Inappropriate instructions, lack of follow-up and lack of
patient-centered care models have been identified as main
reasons for "nonresponse",
leading to drop-out rates of even >
50%. Preservation of corporal smooth muscle with chronic administration
of PDE5i has been reported and there is a substantial body
of evidence for beneficial effects of these drugs on endothelium
and cardiovascular function. Finally, improvement of lower
urinary symptoms after PDE5i administration has been reported
and a possible role on treatment of premature ejaculation
has been proposed. Many new PDE5i are candidates to enter
the market in the forthcoming years. However, pharmacokinetic
differences should be obvious to consider a truly better option
for patients. Patients must be aware of all treatment options
since no ideal treatment exists and physicians must offer
personalized medicine to their patients in the future. The
development and adaptation of a patient-centered care model
in sexual medicine will increase efficacy and safety of current
and future treatments.
[Back to top]
[Purchase
Article]
[PMID:
19860694 PubMed - indexed for MEDLINE]
Phosphodiesterase Type 5 Inhibitors for the Management
of Erectile Dysfunction: Preference and Adherence to Treatment
T. F. Al-Shaiji and G. B. Brock
Erectile dysfunction (ED) is a common medical condition that
has a negative impact on men and their partners. The field
has revolutionised over the last two decades and more treatment
options are available now for the treatment of ED than ever
before. Among available treatment options, the most commonly
prescribed therapies are oral phosphodiesterase type 5 (PDE5)
inhibitors. The first drug in this class, sildenafil citrate,
generally provides patients and their partners with efficacious,
safe, and discreet treatment that rapidly has become the first-line
treatment option. Its successful introduction into clinical
practice was soon followed by the launch of two other PDE5
inhibitors: tadalafil and vardenafil. The existence of these
drugs has resulted in an increase in their marketing. However,
the abundance of choices made the question “which
PDE-5 inhibitor?”
relevant for clinicians, patients and their partners. It is
widely accepted that there are no significant differences
in their safety and efficacy, a fact that has led to the initiation
of studies aiming to evaluate them regarding patient preference.
Nevertheless, the results are rather conflicting. Also a significant
percentage of men initiating treatment switch between inhibitors
or discontinue therapy. This article examines the peer-reviewed
published data addressing patient’s
preference and adherence to ED treatment with PDE5 inhibitors.
It also examines strategies to improve compliance and satisfaction
with treatment.
[Back to top]
[Purchase
Article]
[PMID:
19860695 PubMed - indexed for MEDLINE]
Prophylaxis of Erectile Function After Radical Prostatectomy
with Phosphodiesterase Type 5 Inhibitors
F. Deho, A. Gallina, A. Salonia, A. Briganti, N. Suardi,
G. Zanni, G. Guazzoni, P. Rigatti and F. Montorsi
Erectile dysfunction (ED) is one of the most challenging complications
associated with radical prostatectomy (RP) for clinically
localized prostate cancer. Currently, a broad spectrum of
therapeutic options are available to improve sexual health
after surgical treatment.
Several basic science reports highlighted a potential role
for phosphodiesterase type 5 inhibitors in the prevention
of endothelial damage related to ischemia reperfusion and/or
denervation following surgery. Recent studies have shown that
pharmacological prophylaxis soon after RP can significantly
improve the rate at which erectile function is recovered after
surgery. Use of on-demand treatments for ED in patients who
have undergone RP has been shown to be highly effective. In
this context, pharmacological prophylaxis potentially may
have a significantly expanded role in future strategies aimed
at preserving postoperative erectile function. We
analyzed the factors affecting erectile function after RP
and evaluated the evidence suggesting the role of pharmacological
prophylaxis and treatment of ED after surgery.
[Back to top]
[Purchase
Article]
[PMID:
19860696 PubMed - indexed for MEDLINE]
PDE5 Inhibitors in the Treatment of LUTS
M. J. Speakman
Both lower urinary tract symptoms (LUTS) and erectile dysfunction
(ED) have a negative impact on patients’
quality of life. The co-prescription of two active agents
for these conditions will improve each condition and the addition
of one drug to the other may potentiate the primary response
of the first treatment and thereby improve the QoL of patients.
Several epidemiological studies have indicated that the association
between LUTS and ED is more than a co-incidence of age, with
a possible cause and effect relationship. LUTS is more common
in men with ED and there is a strong relationship between
the severity of LUTS and the degree of erectile difficulty.
Four pathophysiologies have been suggested to explain the
relationship between LUTS and ED. There is a complex interaction
between these mechanisms and there may be additional processes
involved. These are: (1) alteration in nitric oxide levels;
(2) autonomic hyperactivity; (3) changes in the Rho-kinase/endothelin
pathway; and (4) pelvic vasculature atherosclerosis.
Studies of all three easily available PDE-5 inhibitors have
shown improvements in both LUTS and ED in men with significant
problems in both areas without any substantial increase in
side effect profile. Studies have also shown that the greatest
improvements occurred with the combination of an alpha blocker
and PDE-5 inhibitor when compared with either drug alone.
Whilst significant improvements were seen in LUTS symptom
scores, there was no significant improvement in flow rates
with PDE-5 inhibitors when compared with placebo.
High quality basic science studies of PDE-5 inhibitors on
bladder muscle and alpha blocker agents on penile cavernosal
tissue have provided several explanations for their modes
of action. Even so, the mechanism of action of PDE-5 inhibitors
in LUTS remains far from certain.
More well-designed, placebo-controlled studies are needed
to confirm the impact of these drugs, alone or in combination,
on both ED and LUTS. However combination therapy appears appropriate
for patients with both LUTS and ED. At present though, we
should not routinely offer a combination of PDE-5 inhibitors
and alpha blocker for the treatment of LUTS alone.
[Back to top]
[Purchase
Article]
[PMID:
19860697 PubMed - indexed for MEDLINE]
Is There a Role for PDE5 Inhibitors in the Management
of Male Infertility Due to Defects in Testicular or Epididymal
Function?
F. Dimitriadis, P. Tsounapi, M. Saito, T. Watanabe, A.
Sylakos, S. Tsabalas, I. Miyagawa and N. Sofikitis
This review study refers to the possibility to employ
PDE5 inhibitors as an adjunct tool for the therapeutic management
of male infertility. The literature tends to suggest that
PDE5 inhibitors enhance the Leydig cell secretory function
and play a role in the regulation of the contractility of
the tunica albuginea and the epididymis. In addition, the
literature suggests that PDE5 inhibitors increase the prostatic
secretory function that results in an improvement in sperm
motility in several cases. Some studies additionally demonstrate
a role of PDE5 inhibitors in the regulation of sperm capacitation
process. Additional placebo-controlled, randomized, blind
studies are necessary to unequivocally suggest a therapeutic
role of PDE5 inhibitors in the alleviation of semen disorders
and male infertility.
[Back to top]
[Purchase
Article]
[PMID:
19860698 PubMed - indexed for MEDLINE]
PDE5 Inhibitors in Non-Urological Conditions
C. Vlachopoulos, D. Terentes-Printzios, N. Ioakeimidis,
K. Rokkas and C. Stefanadis
Phosphodiesterase type-5 (PDE5) inhibitors are widely used
as first-line therapy for erectile dysfunction (ED). Their
efficacy and safety combined with an increasing understanding
of cyclic guanosine monophosphate (cGMP)-regulated mechanisms,
have triggered a number of attempts to determine their effects
and potential benefits in non-urological conditions.
In recent years, extensive and diverse preclinical
and clinical evidence has been made available. PDE5 inhibition
has shown collateral benefits for a multitude of risk factors
or diseases associated with, or accompanying ED. To date,
PDE5 inhibition has been shown to be effective for the treatment
of idiopathic pulmonary arterial hypertension and both sildenafil
and tadalafil are approved for this indication. However, PDE5
inhibitors appear to have the potential of further expanding
their indications. Importantly, accumulating data show that
the therapeutic potential extends to the cardiovascular, gastrointestinal,
cutaneous and nervous system and that these agents may be
beneficial in a multitude of conditions such as Raynaud’s
phenomenon, heart failure, essential hypertension and stroke.PDE5
inhibitors are a conceptually attractive therapeutic class
of agents with pleiotropic effects. The present review discusses
recent findings regarding the effects of PDE5 inhibitors on
non-urological conditions and highlights current and future
clinical applications beyond ED.
[Back to top]
[Purchase
Article]
[PMID:
19860699 PubMed - indexed for MEDLINE]
Phosphodiesterase-5 Inhibitors: Future Perspectives
Giannitsas Konstantinos and Perimenis Petros
PDE-5 inhibitors were originally studied in cardiovascular
indications but were later developed and approved for on-demand
treatment of erectile dysfunction (ED). A few years ago sildenafil
was approved for the treatment of pulmonary hypertension,
thus renewing interest in cardiovascular applications, and
tadalafil became available in once-daily formulations for
erectile dysfunction management. Given the wide distribution
of phosphodiesterase-5 throughout the body and its involvement
in multiple functions, what can one expect in the future?
To answer this we reviewed studies involving PDE-5 inhibitors
that were published within the past three years and searched
the US National Institutes of Health clinical trial registry
for ongoing ones.
PDE-5 inhibitors are being actively investigated in many disease
states, with interest focusing mainly on urology and cardiovascular
medicine. In urology erectile dysfunction is the primary target,
followed by BPH-related lower urinary tract symptoms. As far
as cardiovascular medicine is concerned, treatment of heart
failure is the indication where PDE-5 inhibitors seem to be
closer to clinical application but preclinical data also support
a role in cardiac preconditioning.
[Back to top]
[Purchase
Article]
[PMID:
19860700 PubMed - indexed for MEDLINE]
Recent Advances of Fluorescent Technologies for Drug
Discovery and Development
Chiranjib Chakraborty, Chi-Hsin Hsu, Zhi-Hong Wen and
Chan-Shing Lin
Recent progresses in the development of fluorescent technologies
become a reliable device for drug discovery research. The
fluorescence tools offer attractive options for an opportunity
to visualize the effects of drug candidates in the cells.
The fluorescent tools, such as fluorescent protein, are regularly
used in a range of drug discovery processes. A better understanding
and use of fluorescent technologies facilitate drug discovery
research faster and can open up new applications. Therefore,
we have provided information about some new generation fluorescent
reagents (GFP and fluorophores). This review illustrates how
fluorescent technologies and fluorescent tools are contributing
to the drug discovery process mainly high-throughput screening
(HTS), disease mechanism based target discovery, disease-genes-based
target discovery, ‘target
classes’
based target candidate discovery, physiology-based drug discovery,
genomics-based drug discovery, target validation
and their future perspectives.
[Back to top]
[Purchase
Article]
[PMID:
19860701 PubMed - indexed for MEDLINE]
Role of Calcitonin Gene-Related Peptide in Gastric
Mucosal Defence and Healing
S. Evangelista
Calcitonin gene-related peptide (CGRP) is a polypeptide produced
by alternative processing of calcitonin gene transcripts and
is endowed with important systemic physiological effects.
The recent characterization of its receptor and the discovery
of stable antagonists has addressed them in the indication
migraine. Beside this, several studies have been focused on
role of CGRP at gastric level. CGRP is considered a marker
of afferent fibers in the upper gastrointestinal tract being
almost completely depleted following treatment with the selective
neurotoxin capsaicin that targets these fibers via transient
receptor potential vanilloid of type-1. The exogenous administration
of the peptide was able to afford protection against experimental
ulcers induced by an increase in gastric secretion. The use
of CGRP knockout mice has let to characterize the endogenous
role of CGRP showing that the local release of this neuropeptide
protects from ethanol injury and favours ulcer healing. Decreased
levels of gastric CGRP-like immunoreactivity (li) were observed
during acetic acid-, cysteamine-, concentrated ethanol- or
water immersion stress-ulcers. Restoration of CGRP-li was
found in animals bearing ulcers in healing status and delayed
healing in mice knockout to CGRP. CGRP was able to release
somatostatin from gastric D cells but its main effects on
the stomach homeostasis rely on local vasodilator action during
increased acid-back diffusion.
[Back to top]
[Purchase
Article]
[PMID:
19860702 PubMed - indexed for MEDLINE]
Fibroblast Growth Factor-2 Antagonist and Antiangiogenic
Activity of Long-Pentraxin 3-Derived
Synthetic Peptides D. Leali, P. Alessi, D. Coltrini, M.
Rusnati, L. Zetta and M. Presta
Angiogenesis and inflammation are closely integrated processes.
Fibroblast growth factor-2 (FGF2) is a prototypic angiogenesis
inducer belonging to the family of the heparin-binding FGF
growth factors. FGF2 exerts its pro-angiogenic activity by
interacting with various endothelial cell surface receptors,
including tyrosine kinase receptors, heparan-sulfate proteoglycans,
and integrins. A tight cross-talk exists between FGF2 and
the inflammatory response in the modulation of blood vessel
growth. Pentraxins act as soluble pattern recognition receptors
with a wide range of functions in various pathophysiological
conditions. The long-pentraxin PTX3 shares the C-terminal
pentraxin-domain with short-pentraxins and possesses a unique
N-terminal domain. These structural features indicate that
PTX3 may have distinct biological/ligand recognition properties
when compared to short-pentraxins. Co-expression of PTX3 and
FGF2 has been observed in different inflammation/angiogenesis-dependent
diseases. PTX3 binds FGF2 with high affinity and specificity.
The interaction prevents the binding of FGF2 to its cognate
tyrosine kinase receptors, leading to inhibition of the angiogenic
activity of the growth factor. This suggests that PTX3 may
exert a modulatory function by limiting the angiogenic activity
of FGF2. An integrated approach that utilized PTX3 fragments,
monoclonal antibodies, and surface plasmon resonance analysis
has identified the FGF2-binding domain in the unique N-terminal
extension of PTX3. On this basis, PTX3-derived synthetic peptides
have been designed endowed with a significant antiangiogenic
activity in vitro and in vivo. They may
provide the basis for the development of novel antiangiogenic
FGF2 antagonists.
|
