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PDE 5 Inhibitors beyond erectile dysfunction
University of Witwatersrand Dr Nathan October
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PDE-5 Inhibitors
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Mechanism of Action
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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
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• Is there any other application for the PDE 5 inhibitors?
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Concentration sites of PDE- 5 • Corpora Cavernosum• Bladder• Prostate• Smooth muscle of systemic vasculature• Cardiac tissue• Brain• Platelets
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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)
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ALTERNATIVE DOSE REGIMEN
• On demand versus daily PDE 5 inhibitors
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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
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• FDA approved it for the treatment of Erectile dysfunction and Pulmonary Hypertension
• The other possible targets are still experimental
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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
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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
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• Causes of endothelial dysfunction
• Hypertension• Smoking• Diabetes Mellitus• Dyslipidemia• Smoking
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Endothelial dysfunction
• Reduction in the bioavailability of vasodilators• Shift towards vasoconstriction• Leads to impairment of endothelial dependant
vasodilatation
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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 ?
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• Markers of endothelial dysfunction • Early intervention • Decrease the risk of a cardiovascular event
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Clinical Indicators of Endothelial dysfunction
• Integrity of the endothelium• Circulating markers and Brachial artery mediated
dilatation
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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)
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Brachial artery mediated dilatation
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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)
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• 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 ?
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Cardiovascular & Endothelial
• Pulmonary Hypertension
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• 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
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• 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
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STUDIES• Anti proliferative factors • Landmark experiment by (Takimoto et al,2005) in mice showed that
chronic PDE 5 inhibitors prevent and reverse cardiac hypertrophy
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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
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• 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)
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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
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Raynaud’s disease
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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
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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
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Urological diseases
• Lower urinary tract symptoms• Overactive bladder• Premature ejaculation• Female sexual dysfunction• Priapism • Peyronie’s disease
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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?
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Priapism
• Stuttering priapism• Hypothesis is that long term treatment c PDE 5
inhibitors may prevent the down regulation of PDE- 5 protein
• Therefore prevent the chronic cGMP accumulation and excessive blood flow in patients with priapism
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Stuttering Priapism
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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
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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)
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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
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Premature Ejaculation
• Hypothesis• Prolongs intravaginal ejaculation latency time• Two theories: central and peripheral
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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)
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Peripheral
• NO/cGMP causes relaxation of corporal smooth muscle
• Relaxation of the smooth muscle of the vas deferens, seminal vesicles, prostate and urethra
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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
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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
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THANK YOU
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References
• Anthony J, Ling X et al. Daily administration of Phosphodiesterase type 5 inhibitors for urological and nonurological conditions, European urology (2007) 52, 990-1005
• 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