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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 11, Number 31, 2005
Contents
Sexual Medicine Research -PDE5 Inhibitors and
Beyond
Executive Editor: Allen D. Seftel
Editorial Pp.3985
The Nitric Oxide Signaling Pathway in the Penis Pp.3987
A.L. Burnett and B. Musicki
[Abstract]
Contractile Mechanisms in Diabetes-Related Erectile
Dysfunction Pp.3995
M.E. DiSanto
[Abstract]
Sonic Hedgehog, the Penis and Erectile Dysfunction:
A Review of Sonic Hedgehog Signaling in the Penis Pp.4011
C.A. Podlasek, C.L. Meroz, H. Korolis, Y. Tang, K.E. McKenna
and K.T. McVary
[Abstract]
Rho-Kinase and RGS-Containing RhoGEFs as Molecular
Targets for the Treatment of Erectile Dysfunction Pp.4029
A.E. Linder, R.C. Webb, T.M. Mills, Z. Ying, R.W. Lewis
and C.E. Teixeira
[Abstract]
The Pleiotropic Effects of Inducible Nitric Oxide
Synthase (iNOS) on the Physiology and Pathology of Penile
Erection Pp.4041
N.F. Gonzalez-Cadavid and J. Rajfer
[Abstract]
Phosphodiesterase Type 5 Inhibitors:Molecular Pharmacology and Interactions
with other Phosphodiesterases Pp.4047
A.D. Seftel
[Abstract]
Endothelial Nitric Oxide Synthase Gene Therapy for
Erectile Dysfunction Pp.4059
T.J. Bivalacqua, B. Musicki, M.F. Usta, H.C. Champion,
P.J. Kadowitz, A.L. Burnett
and W.J.G. Hellstrom
[Abstract]
Animal Models of Ejaculatory Behavior Pp.4069
T. Pattij, B. Olivier and M.D. Waldinger
[Abstract]
General Articles
Magnetic Resonance Contrast Agents: From the Bench
to the Patient Pp.4079
V. Lorusso, L. Pascolo, C. Fernetti, P.L. Anelli, F. Uggeri
and C. Tiribelli
[Abstract]
Artificial O2 Carriers: Status in 2005
Pp.4099
D.R. Spahn and R. Kocian
[Abstract]
Abstracts
[Back to top]
Editorial
Defined as a persistent inability to attain and maintain
an erection adequate for satisfactory sexual activity, male
erectile dysfunction (ED) [1] is an age-related phenomenon
that compromises quality of life for the patient and his partner.
In the Massachusetts Male Aging Study (MMAS), [2] the probability
of ED increased from ~ 40% at age 40 years to ~ 70% at age
70 years. By age 70, only 33% of men reported being entirely
free of erectile difficulties. Several studies have suggested
that in addition to aging, organic or physical ED has a vascular
origin [3, 4]. Mounting evidence has strongly linked ED to
these vascular diseases, further suggesting that ED may be
sentinel sign of cardiovascular disease [5-7]. Timely and
interesting insight into the pathophysiology of sexual dysfunction,
provides possible correlations between sexual dysfunction
and the metabolic syndrome, coronary artery disease and other
vascular diseases [5-9]. Other important and untapped areas
of sexual dysfunction investigation include rapid ejaculation
and ED post therapy for prostate cancer. These 2 areas of
sexual medicine have been catapulted into the limelight as
many men now seek help for an expanding array of sexual problems.
Rapid ejaculation is the most common male sexual malady, yet
we currently lack an FDA-approved therapy for this disease
[10]. Men are now enjoying increased long-term survival due
to advances in prostate cancer therapy [11]. This survivorship
mandates a proactive approach toward treating the comorbidities
associated with prostate cancer therapy such as erectile dysfunction,
as these men live longer and demand a improved quality of
life. Finally, newer modalities of ED therapy, specifically
phosphodiesterase type 5 inhibitors (PDE5i) [12] have provided
a novel approach toward treating male ED, thereby offering
a glimmer of hope for the millions of sufferers of ED. Yet,
only 65-70% of men with ED will find benefit with any of the
currently available PDE5 inhibitors [12]: sildenafil (Viagra),
vardenafil (Levitra) and tadalafil (Cialis), verifying the
need to bring novel therapies for this disease to the forefront.
The data presented herein highlight the important research
work on sexual function being performed at various authoritative
laboratories throughout the world. These mechanistic papers
address the crucial issues underlying the pathophysiology
and potential treatment of male sexual dysfunction. Burnett
et al. [13] discuss the basic physiology of male erectile
function, while Di Santo [14] discusses the pathophysiology
of ED in diabetes. Podlasek et al. [15] detail a
specific pathophysiologic mechanism of ED as it relates to
prostate cancer. Linder et al. [16] review the Rho-kinase
pathway which is another potential pathophysiologic pathway
that revolves around perturbations in the contractile mechanisms
in erection. Gonzalez-Cadavid and Rajfer [17] discuss the
role of iNOS in erectile dysfunction as well as in Peyronie’s
disease. With respect to potential therapies, Seftel [18]
reviews the current oral therapies available for the treatment
of ED. Bivilacqua [19] describes the potential role of gene
therapy as a treatment for ED. Pattij et al. [20]
discuss ejaculatory disorders and potential treatments of
this disorder. These papers underscore the need for continued
research in this understudied area, while detailing the current
state of research in great depth.
References
[1] NIH Consensus Conference. Impotence: NIH Consensus Development
Panel on Impotence. JAMA 1993; 270(1): 83-90.
[2] Feldman HA, Goldstein I, Hatzichristou DG, et al.
Impotence and its medical and psychosocial correlates: results
of the Massachusetts Male Aging Study. J Urol 1994; 151: 54-61.
[3] Lue TF. Erectile dysfunction. N Eng J Med 2000; 342:
1802-1813.
[4] Siroky MB, Azadzoi KM. Vasculogenic erectile dysfunction:
newer therapeutic strategies. J Urol 2003; 170(2 Pt 2): S24-9.
[5] Solomon H, Man J, Wierzbicki AS, O'Brien T, Jackson G.
Erectile dysfunction: cardiovascular risk and the role of
the cardiologist. Int J Clin Pract. 2003; 57(2): 96-9.
[6] Greenstein A, Chen J, Miller H, et al. Does
severity of ischemic coronary disease correlate with erectile
function? Int J Impot Res 1997; 9: 123-1266.
[7] Kloner R, Padma-Nathan H. Erectile dysfunction in patients
with coronary artery disease. Int J Impotence Res 2005; 17:
209?215. doi:10.1038/sj.ijir.3901309. Published online 24
February 2005.
[8] Esposito K, Ciotola M, Marfella R, Di Tommaso D, Cobellis
L, Giugliano D. The metabolic syndrome: a cause of sexual
dysfunction in women. Int J Impotence Res 2005; 17: 224?226.
doi:10.1038/sj.ijir.3901310. Published online 17 February
2005.
[9] Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, MD,
Glasser DB, Rimm EB. Sexual Function in Men Older Than 50
Years of Age: Results from the Health Professionals Follow-up
Study. Ann Intern Med 2003; 139: 161-168.
[10] Laumann EO, Paik A, Rosen RC. Sexual dysfunction in
the United States: prevalence and predictors. JAMA 1999; 281:
537-44.
[11] Walsh PC, Marschke P, Ricker D, Burnett AL. Patient-reported
urinary continence and sexual function after anatomic radical
prostatectomy. Urology 2000; 55(1): 58 61.
[12] de Tejada IS. Therapeutic strategies for optimizing
PDE-5 inhibitor therapy in patients with erectile dysfunction
considered difficult or challenging to treat. Int J Impot
Res 2004; 16(Suppl 1): S40-2.
These are the references from this issue
[13] Burnett AL, Musicki B. The Nitric Oxide Signaling Pathway
in the Penis. Curr Pharm Design 2005; 11(31): 3987-3994.
[14] DiSanto M.E. Contractile Mechanisms in Diabetes-Related
Erectile Dysfunction. Curr Pharm Design 2005; 11(31): 3995-4010.
[15] Podlasek CA, Meroz CL, Korolis H, Tang Y, McKenna KE,
McVary KT. Sonic Hedgehog, the Penis and Erectile Dysfunction:
A Review of Sonic hedgehog Signaling in the Penis. Curr Pharm
Design 2005; 11(31): 4011-4027.
[16] Linder AE, Webb RC, Mills TM, Ying Z, Lewis RW, Teixeira
CE. Rho-Kinase and RGS-Containing RhoGEFs as Molecular Targets
for the Treatment of Erectile Dysfunction. Curr Pharm Design
2005; 11(31): 4029-4040.
[17] Gonzalez-Cadavid NF, Rajfer J. The Pleiotropic Effects
of Inducible Nitric Oxide Synthase (Inos) on the Physiology
and Pathology of Penile Erection. Curr Pharm Design 2005;
11(31): 4041-4046.
[18] Seftel AD. Phosphodiesterase Type 5 Inhibitors: Molecular
Pharmacology and Interactions With Other Phosphodiesterases.
Curr Pharm Design 2005; 11(31): 4047-4058.
[19] Trinity J. Bivalacqua, Biljana Musicki, Mustafa F. Usta,Hunter
C. Champion, Philip J. Kadowitz, Arthur L. Burnett, Wayne
J.G. Hellstrom Endothelial Nitric Oxide Synthase Gene Therapy
for Erectile Dysfunction. Curr Pharm Design 2005; 11(31):
4059-4067.
[20] Pattij T, Olivier B, Waldinger MD. Animal Models of
Ejaculatory Behavior. Curr Pharm Design 2005; 11(31): 4069-4077.
Allen D. Seftel, M.D.
Professor of Urology
Case Western Reserve University
University Hospitals of Cleveland
Cleveland, Ohio
USA
[Back to top]
The Nitric Oxide Signaling Pathway in the Penis
A.L. Burnett and B. Musicki
It is widely accepted that nitric oxide plays an important
role in the biology of the penis, serving most familiarly
as the agent responsible for penile erection. Early investigation
in the field led to the identification of the signaling function
of the molecule in the penis which yields corporal smooth
muscle relaxation fundamental for the erectile response. Ongoing
study of this molecule and its signaling pathway in erectile
tissue has served to revise and clarify its importance. Current
information conveys the prerequisite of the nitric oxide signaling
pathway for penile erection, the regulatory basis for the
generation and actions of nitric oxide in the penis, the diverse
roles of its synthetic enzyme isoforms in penile biology,
and the interaction between nitric oxide and other molecular
pathways operative in the broad context of erection physiology.
Insight into these subject areas has therapeutic relevance
for pathologic conditions of the penis. The purpose of this
review is to highlight the latest areas of investigation related
to the science of nitric oxide in the penis, as a gateway
for considering novel therapeutic strategies for erectile
disorders now and in the future.
[Back to top]
Contractile Mechanisms in Diabetes-Related Erectile
Dysfunction
M.E. DiSanto
Penile tumescence (erection) and detumescence (return to
the flaccid state) are regulated by a complex neurophysiological
process involving the relaxation and contraction, respectively,
of smooth muscle (SM) within the two corpus cavernosum (CC)
of the penis. Failure of the above SM-mediated process to
function properly results in the inability to obtain an erection
sufficient for sexual satisfaction and has been termed erectile
dysfunction (ED). It is predicted that an estimated 322 million
men worldwide will have ED by the year 2025 and, relevant
to this review article, is that roughly 50% of men with diabetes
also have ED. Furthermore, one of the largest classes of nonresponders
to oral phosphodiesterase V (PDE5) inhibitors (the predominant
pharmacological treatment for organic ED) are diabetics. This
review article examines the current knowledge about the contractile
pathways that fine-tune SM tone with particular emphasis on
vascular SM including corpus cavernosum smooth muscle (CCSM).
The role of the contractile apparatus, SM myosin phosphorylation/dephosphorylation
pathways, calcium “sensitization” and “desensitization”
pathways and the main neurotransmitters/modulators responsible
for regulating CCSM contraction are outlined along with how
they are modified or potentially may be modified in response
to diabetes. The overall hypothesis generated from this review
is that an increased CCSM tone, resulting from an enhancement
of contractile mechanisms, may contribute to the higher than
average nonresponse rate of diabetic men to PDE5 inhibitors.
Knowledge gained from this review will hopefully lead to the
generation of drugs that specifically target CCSM contractile
pathways which may prove to have therapeutic usefulness in
treating ED in diabetics either alone or in combination with
existing PDE5 inhibitors.
[Back to top]
Sonic Hedgehog, the Penis and Erectile Dysfunction:
A Review of Sonic Hedgehog Signaling in the Penis
C.A. Podlasek, C.L. Meroz, H. Korolis, Y. Tang, K.E. McKenna
and K.T. McVary
The sinusoid anatomy of the penis is complex and requires
complicated interaction between smooth muscle and endothelium
in order to maintain homeostasis in the adult. The morphogen,
Sonic hedgehog (Shh), is a crucial regulator of these processes,
along with its down stream targets patched (Ptc), Hox, bone
morphogenetic proteins (BMP's), vascular endothelial growth
factor (VEGF) and nitric oxide synthase (NOS). Shh is critical
for patterning and establishing tissue identity of the penis
during embryonic development, is a crucial regulator of penile
postnatal differentiation of the sinusoid morphology of the
corpora cavernosa, and plays a fundamental role in maintaining
sinusoidal structures pertinent to erectile function in the
adult rat. Shh and its targets are active in human penes,
and decreased in human diabetic penes in parallel with observations
in the rat, thus lending clinical significance to the role
of abnormal Shh signaling in erectile dysfunction (ED). Application
of exogenous Shh protein to rat corpora cavernosa, induces
VEGF and NOS proteins, suggesting a potential mechanism through
which decreased Shh protein can cause ED. The studies outlined
in this review provide in depth analysis of the Shh pathway
and signal transduction, its role in penile development, how
Shh signaling is altered in a rat model of ED and neuropathy,
how abnormal Shh signaling can cause ED, and the clinical
significance of the Shh pathway to human ED. These studies
will provide valuable insight, at the molecular level, into
understanding the mechanisms that under lie ED and lead to
new treatment strategies for diabetic impotence.
[Back to top]
Rho-Kinase and RGS-Containing RhoGEFs as Molecular
Targets for the Treatment of Erectile Dysfunction
A.E. Linder, R.C. Webb, T.M. Mills, Z. Ying, R.W. Lewis
and C.E. Teixeira
Erectile dysfunction (ED) is a highly prevalent and often
under-treated condition. Erection is basically a spinal reflex
that can be initiated by recruitment of penile afferents but
also by visual, olfactory and imaginary stimuli. The generated
nervous signals will influence the balance between contractile
and relaxant factors, which control the degree of contraction
of penile corporal cavernosal smooth muscles and, thus, determine
the erectile state of the penis. The different steps involved
in neurotransmission, impulse propagation and intracellular
transduction of neural signals may be changed in different
types of ED. Recent studies have revealed important roles
for the small GTPase RhoA and its effector, Rho-kinase in
regulating cavernosal smooth muscle tone. The RhoA/Rho-kinase
pathway modulates the level of phosphorylation of the myosin
light chain, mainly through inhibition of myosin phosphatase,
and contributes to agonist-induced Ca2+-sensitization
in smooth muscle contraction. Changes in this pathway may
contribute to ED in various patient subgroups (e.g. hypertension,
diabetes, hypogonadism). This review summarizes the importance
of Rho-kinase signaling in the erectile response and introduces
the evidence pointing to RGS-containing Rho-guanine nucleotide
exchange factors (GEFs) as critical mediators of RhoA-GTPase
activation in cavernosal smooth muscle and its possible compartmentalization
in the caveolae. In addition, we suggest that the design of
selective inhibitors of these GEFs might represent a novel
class of pharmacological agents to treat ED.
[Back to top]
The Pleiotropic Effects of Inducible Nitric Oxide
Synthase (iNOS) on the Physiology and Pathology of Penile
Erection
N.F. Gonzalez-Cadavid and J. Rajfer
The contribution of the neuronal and endothelial isoforms
of nitric oxide synthase (nNOS and eNOS, respectively) in
the synthesis of nitric oxide as a mediator of penile erection,
at the levels of both the penile corpora cavernosa and the
hypothalamic regions that control the erectile response, are
well established. More recently, the role of the third NOS
isoform, the inducible NOS (iNOS), has also started to be
elucidated. iNOS does not appear to intervene directly in
physiological penile erection or in its central control, but
its transcriptional induction is postulated to be a key factor
in two opposite related pathological processes, namely neurotoxicity
in critical related regions of the hypothalamus during senescence,
and as a defense mechanism against the aging or injury-associated
fibrosis in the penile corpora cavernosa, the media of the
penile arteries, and the tunica albuginea. By counteracting
fibrosis that impairs cavernosal smooth muscle compliance,
iNOS would protect the erectile tissue. However, further studies
are needed to conclusively evaluate these putative roles in
the two organs involved in reproductive function. In addition,
whether iNOS induction during aging is a major cause in the
net loss of trabecular smooth muscle in the corpora cavernosa
through apoptosis, remains to be elucidated. The overall evaluation
of these conflicting effects is important in order to decide
whether pharmacological iNOS induction, or alternatively NO
donors or L-arginine, may constitute a valid approach to prevent
or treat penile fibrosis and vasculogenic erectile dysfunction.
[Back to top]
Phosphodiesterase Type 5 Inhibitors:Molecular Pharmacology and Interactions
with other Phosphodiesterases
A.D. Seftel
Erectile function is determined by tight regulation of relaxation
or contraction of corpus cavernosal smooth muscle, which is
the result of a long and complex chain of molecular events.
Control of erectile function resides in signaling pathways
of the central and peripheral nervous system, as well as intracellular
events in the penile smooth muscle. Vascular events resulting
in erection have long been understood, and the role of the
signaling pathways of the central and peripheral nervous systems
in erectile function and dysfunction has become increasingly
clear over the last decade. This knowledge has led to the
development and current availability of effective oral treatments
for erectile dysfunction, the selective phosphodiesterase
type 5 (PDE5) inhibitors-sildenafil, vardenafil and tadalafil.
In the past few years we have seen an elucidation of the
molecular events involved in erectile function and dysfunction
and the detailed mechanisms of action by which the specific
PDE5 inhibitors work. A review of those mechanisms helps to
explain the success of the currently available PDE5 inhibitors
and the differences between them and suggests new approaches
for developing potential future novel therapies or refinements
to existing structures that may improve their efficacy, selectivity
and safety profiles.
[Back to top]
Endothelial Nitric Oxide Synthase Gene Therapy for
Erectile Dysfunction
T.J. Bivalacqua, B. Musicki, M.F. Usta, H.C. Champion,
P.J. Kadowitz, A.L. Burnett
and W.J.G. Hellstrom
Basic science research on erectile physiology has been devoted
to investigating the pathogenesis of erectile dysfunction
(ED) and has led to the conclusion that ED is predominately
a disease of vascular origin. It is well recognized that the
incidence of ED dramatically increases in men who suffer from
diabetes mellitus, hypercholesterolemia, and car-diovascular
disease. Endothelial nitric oxide synthase (eNOS) is an important
factor in cardiovascular homeostasis, an-giogenesis, and erectile
function. Given the impact of endothelial-derived nitric oxide
(NO) in vascular biology, a great deal of research over the
past decade has focused on the role of NO synthesis from the
endothelium in normal erectile physiology as well as in disease
states. Loss of the functional integrity of the endothelium
and subsequent endothelial dysfunction plays an integral role
in the occurrence of ED. Therefore, a likely target of gene
therapy for the treatment of ED is eNOS. This communication
reviews the role of eNOS in erectile physiology and discusses
the alterations in eNOS expression in various vascular diseases
of the penis. Putative gene therapy interventions to restore
eNOS expression and subsequent endothelial function may represent
an exciting new therapeutic strategy for the future treatment
of ED.
[Back to top]
Animal Models of Ejaculatory Behavior
T. Pattij, B. Olivier and M.D. Waldinger
Premature ejaculation is generally regarded the most frequent
male ejaculatory complaint and has been considered a psychosexual
disorder with psychogenic aetiology. The efficacy of various
antidepressants, however, to delay ejaculation in men and
to pharmacologically treat premature ejaculation suggests
a strong neurobiological involvement. Most of our current
understanding of the neurobiology and neuroanatomy of sexual
behavior and ejaculatory function has been derived from preclinical
studies using several laboratory species. In the present paper
we will review the various animal models that have been developed
to further study ejaculatory function in the laboratory rat.
In addition, we will briefly review the effects of serotonergic
antidepressants and serotonergic compounds on sexual and ejaculatory
behavior. Together, these preclinical studies may contribute
to a better understanding of the neurobiology of ejaculation
and help the development of novel drug targets to treat ejaculatory
disorders such as premature ejaculation.
General Articles
[Back to top]
Magnetic Resonance Contrast Agents: From the Bench
to the Patient
V. Lorusso, L. Pascolo, C. Fernetti, P.L. Anelli, F. Uggeri
and C. Tiribelli
Magnetic Resonance Imaging is gaining a prominent role in
the routine clinical investigation. To further improve this
technique it is crucial that contrast agents are developed
with more optimal organ specificity. This will not only result
in a better diagnostic efficiency but also in a reduction
of the amount of the agent administered. A combination of
techniques has been employed to increase the target selectivity
of the contrast agent and thereby the feasibility to visu-alize
different organs. The organ targeting is based on the understanding
of the mechanisms involved in the interaction of the agent
with plasma proteins (albumin in particular) as well as the
different membrane transporters involved in the up-take and
in the excretion of the agent from the organ. The physicochemical
properties of the contrast agents play a major role in the
interaction with these various proteins. In this review we
address the relationship between the structure of the contrast
agents and their binding to different plasma proteins and
membrane transporters in different organs, with special reference
to the liver and kidney. The present and potentially future
applications of these concepts in the clinical setting are
also discussed.
[Back to top]
Artificial O2 Carriers: Status in 2005
D.R. Spahn and R. Kocian
Donor blood is a limited resource and its transfusion is
associated with significant adverse effects. Therefore, alternatives
have been searched, the ultimate being artificial oxygen (O2)
carriers. There are two main groups of artificial O2
carriers: hemoglobin based and perfluorocarbon emulsions.
The hemoglobin molecule in hemoglobin based artificial O2
carriers needs to be stabilized to prevent dissociation of
the α2β2-hemoglobin
tetramer into αβ-dimers
in order to prolong intravascular retention and to eliminate
nephrotoxicity. Other modifications serve to decrease O2
affinity in order to improve O2 off-loading to
tissues. In addition, polyethylene glycol may be surface conjugated
to increase molecular size. Finally, certain products are
polymerized to increase the hemoglobin concentration at physiologic
colloid oncotic pressure. Perfluorocarbons are carbon-fluorine
compounds characterized by a high gas dissolving capacity
for O2 and CO2 and chemical and biologic
inertness. Perfluorocarbons are not miscible with water and
therefore need to be brought into emulsion for intravenous
application. Development, product specification, physiologic
effects, efficacy to decrease the need for donor blood in
surgery and side effects of the following products are described:
Diaspirin cross-linked hemoglo-bin (HemAssist), human recombinant
hemoglobin (rHb1.1 and rHb2.0), polymerized bovine hemoglobin-based
O2 carrier (HBOC-201), human polymerized hemoglobin
(PolyHeme®), hemoglobin raffimer (Hemolink™), maleimide-activated
polyethylene glycol-modified hemoglobin (MP4) and perflubron
emulsion (Oxygent™). In addition, enzyme cross-linked
poly-hemoglobin, hemoglobin containing vesicles (nano-dimension
artificial red blood cells) and an allosteric modifier (RSR13)
are discussed. The most advanced products are in clinical
phase III trials but no product has achieved market approval
yet in the US, Europe or Canada.
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