Transcript Nitric Oxide and Its Effect Throughout the Body

Molecular Pathophysiology
of Priapism:
Emerging Targets and New Therapies
Arthur L. (Bud) Burnett, M.D., M.B.A., F.A.C.S.
Patrick C. Walsh Distinguished Professor of Urology
The James Buchanan Brady Urological Institute
Johns Hopkins Medicine
Baltimore, Maryland
Disclosure Statement: In accordance with
ACCME policy on relevant financial
disclosure, I disclose financial relationships
with the following entities: Acorda
Therapeutics, American Medical Systems,
Astellas, Auxilium Inc, Coloplast, Endo
Pharmaceuticals, Genomic Health Inc,
Medispec, National Institutes of Health, New
England Research Institute, Pfizer Inc,
Reflexonic LLC, Urology Times Editorial
Council, Vivus Inc.
Educational Objectives
1. Describe the role of nitric oxide (nitrergic)
signaling in the molecular pathophysiology
of recurrent priapism
2. Assess the application of nitrergic effectors
as a corrective and/or preventative strategy
for recurrent priapism
Science of Recurrent Ischemic Priapism:
Phenomenon No Longer a Medical Mystery
Evolution of understanding based on science
of erection physiology
“Sludging of erythrocytes” is not the
fundamental pathophysiology
Opportunity for prevention or correction
Cycle of Pathogenic Factors
NO Imbalance
-Constitutive Endothelial NO
Bioactivity Decrease
Oxidative Stress
-Reactive Oxygen Species
Generation
Priapism
Penile Vasculopathy
-PDE5 Dysregulation
-Rho-kinase Inactivation
-Lipid Peroxidation
Anoxia
-Cytokine Induction
-Inflammatory Response
Possible Alternative Mechanisms
A2B adenosine receptor-mediated1
– Adenosine deaminase deficiency
Variable coding sequence protein A1mediated2
– Up-regulation of neurogenic ED gene
1.
Mi T, et al. J. Clin. Invest. 118:1491-1501, 2008.
2.
Tong Y, et al. BJU Int. 98:396-401, 2006.
Mechanism of Priapism:
Erections are Uncontrolled
Champion HC et al. PNAS 102:1661-66, 2005.
Burnett AL et al. Urology 67:1043-8, 2006.
Interim Summary
Sickle Cell Disease
PDE5 Inhibitor Therapy
PDE5
eNOS
Penile
Vasculature
ROS ?
Endothelial-NO
PDE5
Priapism
eNOS
Endothelial-NO
Restore Normal
Penile Vascular Homeostasis
A Reversed Nitrate Tolerance
Mechanism?
PDE5 Inhibition for Priapism Prevention:
A Different Therapeutic Scheme
For inducing erections:
For controlling priapism:
– Erectogenic agent
– Molecular signaling
modulator
– Combine with sexual
stimulation
– Unassociated with sexual
stimulation
– Promote cGMP-dependent
cavernosal tissue relaxation
– Restore normal penile
vascular homeostasis
Burnett AL. J Androl 29:3-14, 2007.
Summary of PDE5 Inhibitor
Therapeutic Response
Patient
Etiology
Priapism (Baseline)
Priapism (On Treatment*)
Treatment Duration
24 yo
Hgb SS
3h, daily
Rare
15 mo
37 yo
Hgb SC
3h, daily
Rare
12 mo
22 yo
Hgb SS
>4h (2x)
Rare
8 mo
22 yo
Idiopathic
5h, daily
Occasional
6 mo
35 yo
Idiopathic
>4h (3x)
Occasional
4 mo
24 yo
Hgb SS
2h, 4x weekly
Unchanged
2 mo & d/c’d
25 yo
Idiopathic
2h (5x)
Occasional
3 mo
Priapism improved in 6 of 7 patients after long-term, continuous use of PDE5 inhibitors.
* Sildenafil (25-50 mg po qd) or Tadalafil (10 mg po qod or 5 mg po qd)
Burnett A.L. et al. J Sex Med 2006; 3:1077-84.
PDE5 Inhibitor Clinical Trials:
Translational Evidence
“during open-label assessment, 5 of 8 patients (62.5%)
by intention-to-treat analysis and 2 of 3 patients
(66.7%) by per protocol analysis met this primary
efficacy outcome”
Practical Use of PDE5 Inhibitors for
Priapism Prevention
Sildenafil 25-50mg, daily under conditions of complete
penile flaccidity and absent sexual stimulation
Therapy administered in the morning-time to avoid
priapism risk with nocturnal (i.e. sleep-related)
erections
Because successful response may require 2-3 weeks,
patient self-injection with a sympathomimetic agent
(e.g. phenylephrine) may be necessary temporarily
PDE5 Inhibitor Therapy Perspective
Advantages
– safety
– obviates risks of anti-androgen therapy
Disadvantages
– stigma of erectogenic drug
– requires constant dosing
– expense
– not uniformly successful
Proposed Therapeutic Strategies
PDE5 downregulation
– PDE5 inhibitors1,2
– NO releasing compounds3
Adenosine deaminase deficiency
– PEG-ADA (ADA enzyme therapy)4
Oxidative stress
– NADPH oxidase inhibitor5
1.
2.
3.
4.
5.
Burnett AL et al. J Sex Med 2006;3:1077-1084
Bivalacqua TJ et al. PLoS One 2013; 8
Lagoda G et al. FASEB J 2013
Mi T et al. J Clin Invest 2008;118:1491-1501
Musicki et al. J Sex Med 2013 (in press)
C6’ treatment corrects aberrant PDE5 and NO signaling in Sickle mouse penis (left)
and restores normal erectile function in dNOS-/-mice (right).
FASEB J. 28: 76-84,2014.
Dysregulatory Erection Physiology:
Mechanisms at Multiple Control Levels
Central and peripheral neurotransmission
Paracrine agency
Hormonal axis
Testosterone Replacement
for the Treatment of
SCD-associated Priapism:
Hypothesis
A decline in androgen levels and actions contributes to the
molecular derangements associated with priapism and,
conversely, optimizing androgenic status promotes
regulatory molecular mechanisms that protect against
priapism. Testosterone replacement therapy particularly to
achieve moderate eugonadal levels of testosterone is “not” a
risk for causing priapism.
Testosterone Replacement in Sickle Cell Mice:
Preliminary Findings
PDE5 expression is decreased in penes of homozygote SCD mice
Testosterone replacement in homozygote SCD mice attenuates the
priapism phenotype
Nitrergic Mechanisms of Priapism
Black Arrows = Mechanism of penile erection
Grey Text = Current therapeutic approaches
White Text = Potential therapeutic approaches
NO = nitric oxide; NOS = nitric oxide synthase; PDE5 = phosphodiesterase
type 5; PDE5i = PDE5 inhibitor; TRT= Testosterone replacement therapy
Conclusions
Corrective and/or preventative strategies for
recurrent priapism will arise from ongoing
study of the molecular pathophysiology of this
disorder
Targeting the aberrant nitric oxide signaling
pathway in the penis and developing nitrergic
effectors may offer an effective clinical strategy
for managing recurrent priapism
Priapus, God of Fertility and Gardens
House of Vittei, Ruins of Pompei