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Premature Ejaculation (PE) And
new drug for treatment of PE
Mahdavi RProfessor of Urology and Renal Transplantation
March 2009
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Anatomical structures involved in ejaculation and the central
serotonergic of ejaculation
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Definition (1)
Consensus on definition of PE
1) The Second International Consultation on Sexual and
Erectile Dysfunction defined PE as ‘ejaculation with
minimal stimulation and earlier than desired, before or
soon after penetration, which causes bother or
distress, and over which the sufferer has little or no
voluntary control’
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Definition(2)
2) The international society for sexual medicine (ISSM)
Definition for life-long PE : Premature ejaculation is a
male sexual dysfunction characterized by ejaculation
which always or nearly always occurs prior to or within
about one minute of vaginal penetration; and inability
to delay ejaculation on all or nearly all vaginal
penetrations; and negative personal consequences,
such as distress, bother, frustration and/or the
avoidance of sexual intimacy
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Premature ejaculationclassification
a) Life long (primary) : occurred too fast before
vaginal penetration or < 1-2 minutes
b) Acquired PE (secondary): time to
ejaculation is short but not as fast as in life
long
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Epidemiology ofPremature ejaculation
PE is the most male sexual dysfunction
Prevalence rate : 20-30% overall
Prevalence of life long PE with IELT
(Intra Vaginal Ejaculatory Latency Time)
< 1-2 minutes : 2-5%
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Risk factors and PE (hypothesis)
a) Anxiety
b) Penile hypersensitivity
c) Serotonin receptor dysfunction
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The prevalence of
Premature ejaculation is
not affected by age or
countries
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Percentage of men reporting symptoms of PE in the PEPA
survey, by country and age group
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Side effects of Premature ejaculation
Effect on self-confidence and relationship
with partner
Mental distress
Anxiety
Embarrassment and depression
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Most men with premature
ejaculation do not seek
help
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Diagnostic workup
Medical and sexual history include :
a) Type of PE: Primary or secondary
b) Specific circumstance or specific partner or consistent
c) Length of time of ejaculation
d) Degree of sexual stimulus
e) Impact PE on sexual activity and QoL
f) Drug use or abuse
g) To distinguish PE from ED
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Diagnostic workup
Physical examination include : examination of
vascular , endocrine , neurologic system
Laboratory or physiological testing should be
specific finding from history or physical
examination
Continue:
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Diagnostic workup
In every day clinical practice self-
estimated IELT (intra vaginal ejaculatory
latency time) is sufficient but stop watch-
measured IELTs is necessary in clinical
trials.
Continue:
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Relationships among
measures of PE
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Treatment of Premature ejaculation
First-line treatment: Which ?
Psychological / behavioral sterategies
Topical anesthetic agent
Selective serotonin reuptake inhibitors
Phosphodiesterase types inhibitors
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Psychological / behavioral therapy
Stop-start program ( Semans technique ) or
squeeze technique (Masters – Jonson
technique)
Masturation before intercourse in younger
men
Overall success rate 50-60%
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Topical anesthetic agents
lidocaine-prilocaine cream ( 5% ) 20-30 minutes
before intercourse
To apply condom for prevention vaginal wall
numbnes in the partner
SS-cream ( made from 9 herbs ) apply 0.2 gr /
1 hour before intercourse
Side effect : mild local burning and mild pain in 18.5% of
partners
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Premature ejaculation and role of serotonin
Current evidence suggests that PE is a
neurobiological phenomen
Cerebral and their neurotransmiters like
serotonin, dopamine, oxytocine has a key role in
ejaculation and PE
In PE cases probably there is a low synaptic
levels of serotonin in CNS because of variation
in serotonin receptor sensitivity
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Proposed mechanism of action of Dapoxetine
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Selective serotonin reuptake inhibitors (SSRIs): First treatment of Premature
ejaculation
Paroxetine
Sertraline (Asentra)
Dapoxetine
These agents act to decrease the rate of removal of
serotonin from synaptic cleft , thus causing an
elevation in serotonergic activity at the synapse and
prolong IELTs.
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Selective serotonin reuptake inhibitors
(SSRIs)
Paroxetine
Sertraline (Asentra)
At least 1-2 weeks administration needs for
paroxetine and sertraline to prolong IELTS
Half-lives elimination of these agents 5h to 4days
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Pharmacokinetic profiles of Dapoxetine and
longer – acting SSRIs
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Dapoxetine for the on-demand
treatment of Premature ejaculation
It is short SSRI and administrated as
on-demand (PRN)
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Mechanism action of Dapoxetine
Inhibits the ejaculatory expulsion reflex in
the rate by cutting at supraspinal level
resulting in pudendal motor neuron reflex
discharge latency and a reduction in
PRMD duration
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Dapoxetine:Rapid absorption and elimination
Maximum plasma concentration 1-2 hours
after single dose 30-60 mg/day
By 24% plasma concentration ↓ 5% of the
peak
Daily accumulation is minimal
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Metabolism and excretion of
Dapoxetine
99% is bound to protein (in vitro)
Metabolized in liver (CYP 450)
Metabolites were eliminated in the urine
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The dapoxetine clinical development
program
5 double-blind-placebo controlled phase III
clinical studies were performed (a total
6081 subjects were randomized) in 16
countries
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Results of these studies at the 24
weekend point :
1- Dapoxetine significantly increased
ejaculatory latency time (IELT)
2- Dapoxetine improved control over
ejaculation and reduced distress relatad to
ejaculation
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Satisfaction with
sexual intercourse
with Dapoxetine
30 and 60 mg and
placebo in the
international study
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At the week 24 end point
Approximately 58% and 72% of subjects
receiving Dapoxetine 30 and 60 mg
reported that PE was slightly better, much
better compared with 32% of subjects
receiving placebo (p < o.ooo1)
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Mean average IELT (min) during traetment with Dapoxetine
30 and 60 mg or placebo over time in the international study
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Overall adverse events of Dapoxetine
The most common adversa events with dapoxetine are
nausea(16%), headache(8%) and dizziness(7.7%)
Orthostatic hypotension (O.H)
Precaution:
a) History of O.H
b) Who taking α-blocker antagonist
c) Nitrate
d) Phosphodiesterase (PDF) 5-inhibitor
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Overall adverse events of Dapoxetine
Syncope: especially in patient with
underlying structural cardiovascular
disease
Withdrawal syndrome?
Continue:
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Dapoxetine:
Contraindications
Hypersensitivity
Presence of significant pathologic cardiac
condition :
a) Heart failure (class II-IV)
b) Second or third degree A-V block or sick sinus
syndrome
c) Significant IHD or valvular disease
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Dapoxetine:
ContraindicationsUse of monoaminoxidase inhibitors, thioridazine and
agents with serotonergic effect like :
- Norepinephrine
- Tramadol
- Lithium
Concomitant treatment with certain drugs that strong
effects on CYPA4 like : ketoconazole, itraconazole
Moderate and severe hepatic impairment
Severe renal impairment
Continue:
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Dapoxetine
Precaution and drug interaction
Caution is advised in patients taking moderate
CYP3AU inhibitors like: Erythromycin,
Clarithromycin, Verapamil, Diltiazem
Dose of Dapoxetine must be restricted to 30mg
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Dapoxetine Precaution and drug interaction
Relative contraindication in patients with history of
mania / hypomania or bipolar disorder
Unstable seizure (dapoxetine lower seizure
threshold)
Psychiatric disorder
Ethanol (alcohol) : increase alcohol-related effects
and increase the risk of accidental injury
Driving or operating hazardous machinery
Continue:
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Perceived control
over ejaculation
and personal
distress related to
ejaculation
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Perceived control
over ejaculation
with Dapoxetine
30 and 60 mg and
placebo in the
international study
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CGI of change in
PE al the week 24
endpoint (LPOCF)
with Dapoxetine
30 and 60 mg and
placebo in the
international study
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Satisfaction with
sexual intercourse
and interpersonal
difficultly related
to ejaculation
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Important patient information
Take Dapoxetine 1 to 3 hours before sexual activity
Take Dapoxetine with at least one full glass of water
Do not take Dapoxetine more than once every 24
hours
Do not combine Dapoxetine with alcohol or
recreational drugs
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Premature Ejaculation and sildenafil
IELT was not significantly improved ??
However:
- Increase confidence
- Reduce anxiety
- Increase the perception of ejaculatory control
- Increase the overall sexual satisfaction
Sildenafil + SSRI is superior to SSRI
monotherapy
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