PDE 5 Inhibitors beyond erectile dysfunction - PowerPoint Presentation

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PDE 5 Inhibitors beyond erectile dysfunction

University of Witwatersrand Dr Nathan OctoberSlide2

PDE-5 InhibitorsSlide3

Mechanism of ActionSlide4

Approved and emerging PDE 5 inhibitors

CompoundCompanySildenafilPfizerVardenafil

Bayer AGTadalafilEli Lilly

Udenafil

Dong Pharmaceutical

Co Ltd

Avanafil

Tanabe

Seiyaku, licence by

Vivus

SLX-2101

Surface logicsSlide5
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Is there any other application for the PDE 5 inhibitors?Slide7

Concentration sites of PDE- 5

Corpora CavernosumBladderProstateSmooth muscle of systemic vasculatureCardiac tissueBrainPlateletsSlide8

PDE 5 inhibitors

It’s relatively safe and efficientAgents are selective (Sildenafil and vardenafil cross react slightly with PDE-6 and tadalafil with PDE-11) Slide9

ALTERNATIVE DOSE REGIMEN

On demand versus daily PDE 5 inhibitors Slide10

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 experimentalSlide12

Possible targets

Non-urological Cardiovascular diseases Central nervous systemUrological Lower urinary tract symptoms Priapism Premature ejaculation Overactive bladder Female sexual arousal dysfunction Peyronie’s disease Slide13

Cardiovascular diseases

Endothelial dysfunctionErectile dysfunction is a vascular disorder in most casesEndothelial dysfunction initial step in artherosclerosis of the penile vasculature and systemic vasculatureSlide14
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Causes of endothelial dysfunction

HypertensionSmokingDiabetes MellitusDyslipidemiaSmokingSlide16

Endothelial dysfunction

Reduction in the bioavailability of vasodilatorsShift towards vasoconstrictionLeads to impairment of endothelial dependant vasodilatationSlide17

Endothelial dysfuntion

cont…Conclusions Onset of sexual dysfunction is a marker of subclinical vascular diseasePredictor of future cardiovascular eventEarly recognition and treatment of endothelial dysfunction may prevent future ischaemic heart disease PDE 5 inhibitors as a therapeutic tool in endothelial dysfunction ?Slide18

Markers of endothelial dysfunction

Early intervention Decrease the risk of a cardiovascular eventSlide19

Clinical Indicators of Endothelial dysfunction

Integrity of the endotheliumCirculating markers and Brachial artery mediated dilatation Slide20

Endothelial dysfunction cont…

Circulating markersIndicates the integrity of the endotheliumActivated endothelial cells – indicates early development of artherosclerosisNamely : 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 unknownhsCRP

prognostic value for future cardiovascular events (

Bassuk

et al,2004) Slide21

Brachial artery mediated dilatationSlide22

Studies

PDE 5 inhibitor treatment have shown a decreased infarct size after ischemia-reperfusion injury in animal modelsChronic PDE 5 inhibitors increases endothelium dependant flow and improve endothelium function in patients at risk for myocardial injury (Foresta et al,2006)Slide23

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 ?Slide24

Cardiovascular & Endothelial

Pulmonary HypertensionSlide25

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 trialResults - well tolerated , improved exercise capacity and haemodynamic parametersImproving the cardiac output by decreasing the pulmonary arterial pressureApproved by FDA in 2005 for treatment of PAHSlide26

Congestive heart failure

Vasoconstriction is a pathophysiological hallmark of congestive heart failureHypothesis – PDE 5 inhibitors causes vasodilation most prominently in the pulmonary vasculatureIncrease the compliance of the larger vessels Therefore decreasing the afterload, increases the cardiac output Slide27

STUDIES

Anti proliferative factors Landmark experiment by (Takimoto et al,2005) in mice showed that chronic PDE 5 inhibitors prevent and reverse cardiac hypertrophySlide28

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 unknownSlide29

Hypertension

PDE 5 inhibitors due to it’s vasodilatory effect are a possible treatment option for hypertensionStudiesPDE 5 Inhibitors decrease the BP average 9/8 mm Hg (systolic/diastole) (Jackson et al, 2005) Slide30

CVA

Multiple studies in rats confirmed the neurogenic effect of PDE 5 inhibitorsTreatment with Sildenafil for 7 days after an ischaemic event in the brain of ratsResults – 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 strokeSlide31

Raynaud’s diseaseSlide32

Raynaud’s disease

Increasing evidence that NO/cGMP plays an important roleOpen label pilot study investigated the effects of vardenafil on clinical symptoms in 40 patients c Raynaud phenomenonDoppler 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 patientsSlide33

Memory and Cognition

PDE 5 inhibitors showed increase in the memory performance of rodentsHowever the results in humans have only been studied sporadicallyFurther trials requiredSlide34

Urological diseases

Lower urinary tract symptomsOveractive bladderPremature ejaculationFemale sexual dysfunctionPriapism Peyronie’s diseaseSlide35

LOWER URINARY TRACT SYMPTOMS

PDE 5 inhibitors have shown to relax human prostate tissue in vitroClinical trials - patient treated with 100mg Sildenafil or tadalafil 20 mg daily or placebo for 12 weeksIPSS was reduced with an average of 6.3 in the treatment group compared to 1.9 in the placebo groupNo change in the urodynamics of these patients (Mcvary.et al)Additional treatment option? Slide36

Priapism

Stuttering priapismHypothesis 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 priapismSlide37

Stuttering PriapismSlide38

Peyronie’s Disease

Cyclic GMP has been found to be anti fibrotic in Peyronie’s diseaseLong term treatment with PDE 5 inhibitors prevent plaque formation in rat modelsPDE 5 is expressed in tunical and Peyronie’s disease fibroblasts (Valente et al,2005)Treatment option further human studies requiredSlide39

Female sexual dysfunction

Increase blood flow in the clitoral cavernosum and vagina Hypothesis it may benefit women with female sexual dysfunctionThe results were not very encouragingModerate effect in pre and post menopausal females (Caruso et al, 2006)Slide40

Overactive Bladders

Mechanism of actionDecrease 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 dogsSlide41

Premature Ejaculation

HypothesisProlongs intravaginal ejaculation latency timeTwo theories: central and peripheralSlide42

Central

NO/cGMP in the medial pre optic area of the brain causes erection and decrease central sympathetic output in the animal modelsAnimal modelsAdministration of PDE 5 inhibitors increase cGMP in the medial pre optic area (Sato et al,2007)Slide43

Peripheral

NO/cGMP causes relaxation of corporal smooth muscle Relaxation of the smooth muscle of the vas deferens, seminal vesicles, prostate and urethraSlide44

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 creamResults –Sildenafil was not more effective than the placebo EMLA cream alone was as effective as EMLA cream and Sildenafil Slide45

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 Slide46

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, 990-1005P sander, J Hutter, H Tinel et al. PDE 5 inhibitors beyond erectile dysfunction, International journal of impotence research (2007) 19, 533-543P Montsori, P Ravagnani, S Galli et al. The triad of Endothelial Dysfunction, Cardiovascular Disease and

Erectile Dysfunction Clinical implications, European urology (2009) 8, 58-66M Guazzi et al. Clinical use of

phosphodiesterase

inhibitors in CHF, Circulation heart failure (2008) 1, 272-280