Transcript PDE 5 - MM3 Admin

PDE 5 Inhibitors beyond erectile
dysfunction
University of Witwatersrand
Dr Nathan October
PDE-5 Inhibitors
Mechanism of Action
Approved and emerging PDE 5
inhibitors
Compound
Company
Sildenafil
Pfizer
Vardenafil
Bayer AG
Tadalafil
Eli Lilly
Udenafil
Dong Pharmaceutical Co Ltd
Avanafil
Tanabe Seiyaku, licence by Vivus
SLX-2101
Surface logics
• Is there any other application for the PDE 5
inhibitors?
Concentration sites of PDE- 5
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Corpora Cavernosum
Bladder
Prostate
Smooth muscle of systemic vasculature
Cardiac tissue
Brain
Platelets
PDE 5 inhibitors
• It’s relatively safe and efficient
• Agents are selective (Sildenafil and vardenafil cross
react slightly with PDE-6 and tadalafil with PDE-11)
ALTERNATIVE DOSE REGIMEN
• On demand versus daily PDE 5 inhibitors
Daily PDE 5 inhibitors in Erectile
dysfunction
• Multiple studies – improved outcome
> Patients with poor response to on demand
PDE 5 inhibitors
> Diabetic patients
> Post radical prostatectomy patients
Triggered multiple attempts to find alternative applications
for your PDE 5 inhibitors
• FDA approved it for the treatment of Erectile
dysfunction and Pulmonary Hypertension
• The other possible targets are still experimental
Possible targets
• Non-urological
Cardiovascular diseases
Central nervous system
• Urological
Lower urinary tract symptoms
Priapism
Premature ejaculation
Overactive bladder
Female sexual arousal dysfunction
Peyronie’s disease
Cardiovascular diseases
• Endothelial dysfunction
• Erectile dysfunction is a vascular disorder in most
cases
• Endothelial dysfunction initial step in artherosclerosis
of the penile vasculature and systemic vasculature
• Causes of endothelial dysfunction
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Hypertension
Smoking
Diabetes Mellitus
Dyslipidemia
Smoking
Endothelial dysfunction
• Reduction in the bioavailability of vasodilators
• Shift towards vasoconstriction
• Leads to impairment of endothelial dependant
vasodilatation
Endothelial dysfuntion cont…
• Conclusions
• Onset of sexual dysfunction is a marker of subclinical
vascular disease
• Predictor of future cardiovascular event
• Early recognition and treatment of endothelial
dysfunction may prevent future ischaemic heart
disease
• PDE 5 inhibitors as a therapeutic tool in endothelial
dysfunction ?
• Markers of endothelial dysfunction
• Early intervention
• Decrease the risk of a cardiovascular event
Clinical Indicators of Endothelial
dysfunction
• Integrity of the endothelium
• Circulating markers and Brachial artery mediated
dilatation
Endothelial dysfunction cont…
• Circulating markers
• Indicates the integrity of the endothelium
• Activated endothelial cells – indicates early development
of artherosclerosis
• Namely : ADAM (Assymmetric dimethyl arginine)
hsCRP (High sensitivity c reactive protein)
• Evidence that ADAM decrease the production of NO
(Thum T et al, 2005)
• Exact pathological role of hsCRP unknown
• hsCRP prognostic value for future cardiovascular events
(Bassuk et al,2004)
Brachial artery mediated dilatation
Studies
• PDE 5 inhibitor treatment have shown a decreased
infarct size after ischemia-reperfusion injury in
animal models
• Chronic PDE 5 inhibitors increases endothelium
dependant flow and improve endothelium function
in patients at risk for myocardial injury (Foresta et
al,2006)
• Endothelial dysfunction is an early marker for
atherosclerosis (Bocchio et al,2004)
• Endothelial dysfunction patient had a two field
increase in the risk of acute myocardial infarction
compared to non-endothelial dysfunction patients
(Blumentals et al,2005)
• Cardio protective role is unclear ?
Cardiovascular & Endothelial
• Pulmonary Hypertension
• Animal models : PDE 5 (Sildenafil) reduces pulmonary
arterial pressure and right heart hypertrophy
• Clinical study
• SUPER 1 (Sildenafil use in pulmonary hypertension),
multinational randomized controlled trial
• Results - well tolerated , improved exercise capacity
and haemodynamic parameters
• Improving the cardiac output by decreasing the
pulmonary arterial pressure
• Approved by FDA in 2005 for treatment of PAH
• Congestive heart failure
• Vasoconstriction is a pathophysiological hallmark of
congestive heart failure
• Hypothesis – PDE 5 inhibitors causes vasodilation
most prominently in the pulmonary vasculature
• Increase the compliance of the larger vessels
• Therefore decreasing the afterload, increases the
cardiac output
STUDIES
• Anti proliferative factors
• Landmark experiment by (Takimoto et al,2005) in mice showed that
chronic PDE 5 inhibitors prevent and reverse cardiac hypertrophy
Studies
• Patients c an ejection fraction of 35% a single dose of
50mg sildenafil improved cardiac performance by
decreasing peripheral resistance (Hirata et al)
• Sildenafil-increased endothelium dependant, flow
mediated vasodilation in patients in chronic heart
failure (Katz et al, 2000)
• The effect of left ventricular function is unknown
• Hypertension
• PDE 5 inhibitors due to it’s vasodilatory effect are a
possible treatment option for hypertension
• Studies
• PDE 5 Inhibitors decrease the BP average 9/8 mm Hg
(systolic/diastole) (Jackson et al, 2005)
CVA
• Multiple studies in rats confirmed the neurogenic effect of
PDE 5 inhibitors
• Treatment with Sildenafil for 7 days after an ischaemic
event in the brain of rats
• Results – increase endothelial proliferation and
synaptogenesis, increase functional recovery in the rodents
(Zhang et al)
• However in humans PDE 5 inhibitors due to it’s vasodilatory
effect are contraindicated in the first 6 months post stroke
Raynaud’s disease
Raynaud’s disease
• Increasing evidence that NO/cGMP plays an important role
• Open label pilot study investigated the effects of vardenafil
on clinical symptoms in 40 patients c Raynaud
phenomenon
• Doppler flow studies revealed increase in blood flow in 75%
of the patients (Caglayan et al, 2006)
• Double blind placebo controlled trial ( Fries et al, 2005)
showed decrease in frequency of the attacks and duration
with capillary blood flow increasing in all the patients
Memory and Cognition
• PDE 5 inhibitors showed increase in the memory
performance of rodents
• However the results in humans have only been
studied sporadically
• Further trials required
Urological diseases
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Lower urinary tract symptoms
Overactive bladder
Premature ejaculation
Female sexual dysfunction
Priapism
Peyronie’s disease
LOWER URINARY TRACT SYMPTOMS
• PDE 5 inhibitors have shown to relax human prostate
tissue in vitro
• Clinical trials - patient treated with 100mg Sildenafil or
tadalafil 20 mg daily or placebo for 12 weeks
• IPSS was reduced with an average of 6.3 in the treatment
group compared to 1.9 in the placebo group
• No change in the urodynamics of these patients
(Mcvary.et al)
• Additional treatment option?
Priapism
• Stuttering priapism
• Hypothesis is that long term treatment c PDE 5
inhibitors may prevent the down regulation of PDE5 protein
• Therefore prevent the chronic cGMP accumulation
and excessive blood flow in patients with priapism
Stuttering Priapism
Peyronie’s Disease
• Cyclic GMP has been found to be anti fibrotic in
Peyronie’s disease
• Long term treatment with PDE 5 inhibitors prevent
plaque formation in rat models
• PDE 5 is expressed in tunical and Peyronie’s disease
fibroblasts (Valente et al,2005)
• Treatment option further human studies required
Female sexual dysfunction
• Increase blood flow in the clitoral cavernosum and
vagina
• Hypothesis it may benefit women with female sexual
dysfunction
• The results were not very encouraging
• Moderate effect in pre and post menopausal females
(Caruso et al, 2006)
Overactive Bladders
• Mechanism of action
• Decrease the tone of the bladder
• (Sandner P et al) showed a decrease in the tone of
the muscle strips of the male beagle dog between
70-20 %.
• Decreasing the frequency of urination and increases
the volume of the bladder of conscious dogs
Premature Ejaculation
• Hypothesis
• Prolongs intravaginal ejaculation latency time
• Two theories: central and peripheral
Central
• NO/cGMP in the medial pre optic area of the brain
causes erection and decrease central sympathetic
output in the animal models
• Animal models
• Administration of PDE 5 inhibitors increase cGMP in
the medial pre optic area (Sato et al,2007)
Peripheral
• NO/cGMP causes relaxation of corporal smooth
muscle
• Relaxation of the smooth muscle of the vas deferens,
seminal vesicles, prostate and urethra
Studies
• However no convincing evidence that on demand or daily PDE
5 inhibitors play a role in the treatment of premature
ejaculation
• ( Atan et al,2006)) randomized control trial compared
Placebo alone
Sildenafil alone
EMLA cream alone
Sildenafil and EMLA cream
• Results –Sildenafil was not more effective than the
placebo
EMLA cream alone was as effective as EMLA
cream and Sildenafil
Conclusion
• Daily low dose PDE-5 inhibitors may play a role in
certain disease processes
• Drawback is the costs involved
• Further multinational randomized control trials or
prospective studies are required to define the exact
role of PDE-5 Inhibitors
THANK YOU
References
• Anthony J, Ling X et al. Daily administration of
Phosphodiesterase type 5 inhibitors for urological and
nonurological conditions, European urology (2007) 52, 9901005
• P sander, J Hutter, H Tinel et al. PDE 5 inhibitors beyond
erectile dysfunction, International journal of impotence
research (2007) 19, 533-543
• P Montsori, P Ravagnani, S Galli et al. The triad of
Endothelial Dysfunction, Cardiovascular Disease and
Erectile Dysfunction Clinical implications, European urology
(2009) 8, 58-66
• M Guazzi et al. Clinical use of phosphodiesterase inhibitors
in CHF, Circulation heart failure (2008) 1, 272-280