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Dapoxetine – A New Pharmacological Treatment for Premature Ejaculation
concentration of serotonergic neurones, plays a strong inhibitory role treatment response of PE in clinical studies.
23,25
Some clinical studies
in the control of ejaculation,
9,10
and the periaqueductal grey has been including this end-point have used a stopwatch operated by the
shown in an experimental animal system to control the expulsion patient or his partner, while others have used estimates of latency
reflex.
11
Mid-brain structures also regulate ejaculation, but further based on patient and/or partner recall. However, use of this variable
investigations are required to reveal additional mechanistic details. alone may be insufficient for evaluating patients with PE because
the IELT does not reflect important subjective components of this
Regulation of the ejaculatory reflex at the level of the spinal cord multidimensional condition, e.g. control over ejaculation and
requires that co-ordinated neurochemical inter-relationships take distress. Data from some studies
22,26
indicate that the IELT alone is
place at different levels of the neuraxis.
12,13
Several neurotransmitter not sufficient for accurately assigning PE status. In large
systems distributed throughout the supraspinal and spinal regions observational studies that used the DSM-IV-TR as a diagnostic tool
have been implicated in this process, with the serotonin (5-HT) and for PE,
22,26
patient-reported outcomes of control over ejaculation and
dopaminergic neurones playing a primary role,
14
and other neuro- personal distress were found to be important measures directly
transmitters – including acetylcholine, adrenaline, neuropeptides, related to PE.
27
For example, results from one study
22
of men in the
oxytocin, γ-aminobutyric acid and nitric oxide – acting secondarily.
15,16
US showed that significantly more subjects with PE than without
Although the hypothesised spinal and supraspinal pathways of the reported having ‘very poor’ or ‘poor’ control over ejaculation (72
neurotransmitter network involved in the ejaculatory process are versus 5%; p<0.001), and these percentages were similar between
documented, the precise role of the various substances in the trials of men in the US
22
and the EU.
28
Furthermore, more subjects in
ejaculatory reflex is difficult to define because of the wide range of the PE group reported ‘quite a bit’ or ‘extremely’ for personal
sexual variables besides ejaculation that are affected, the distress (64 versus 4%; p<0.001) compared with the non-PE group.
heterogeneity of results shown in different species, the variation of Analyses of these data showed that measures of control over
activity depending on the site in the central nervous system (CNS) ejaculation and personal distress were reliable, valid and efficient
where the transmitter acts and the variety of receptor subtypes measures of PE outcomes, and therefore should be used in
putatively involved. conjunction with the IELT to assess PE.
29,30
Furthermore, these results
in men in the US were recently confirmed in a similar study of men
5-HT appears to be a key mediator in the neurophysiology of from five European countries.
26
ejaculation.
15,17
5-HT neurones express somatodendritic autoreceptors
(including 5-HT
1A
receptors present in the mesencephalic and medullary Continuous versus On-demand Administration
raphe nuclei), pre-synaptic autoreceptors (5-HT
1B
and 5-HT
1D
), 5-HT of Selective Serotonin Re-uptake Inhibitors for
signalling receptors (e.g. 5-HT
2C
) and 5-HT re-uptake transporters, each Managing Premature Ejaculation
of which has different effects on cellular activation and 5-HT Continuous daily dosing of selective serotonin re-uptake inhibitors
signalling.
12,18
In general, activation of 5-HT
1A
autoreceptors decreases 5- (SSRIs) is effective in delaying ejaculation. However, this approach
HT release by the pre-synaptic neurones, providing a negative feedback increases exposure to medication, thereby increasing the likelihood
mechanism for 5-HT neurotransmission.
5,18
Signal transduction through of side effects. Conversely, it was suggested that the efficacy of
5-HT
1A
and 5-HT
2C
receptors plays a key role in regulating ejaculation at on-demand administration of conventional SSRIs indicated for the
the central level.
19
Activation of post-synaptic 5-HT
2C
or 5-HT
1B
receptors treatment of depression might be limited by inherent neuro-
prolongs ejaculatory latency, whereas activation of pre-synaptic 5-HT
1A
transmission feedback mechanisms.
21,31
A few studies evaluated the
autoreceptors, which inhibit 5-HT release, decreases ejaculatory use of SSRI antidepressants with as-needed dosing, but the study
latency.
13,19
Subcutaneous administration of the 5-HT
1B
receptor agonists designs were not rigorous.
32–35
With episodic administration, SSRIs
anpirtoline and mtrifluoromethylphenylpiperazine and systemic, acute acutely block 5-HT re-uptake by 5-HT transporters in pre-synaptic
administration of the 5-HT
2C
agonist 2,5-dimethoxy-4-iodoamphetamine neurones,
36,37
resulting in an increase in synaptic 5-HT levels.
have been shown to impair ejaculation in rats.
13
It was suggested that PE However, this increased 5-HT also activates 5-HT
1A
somatodendritic
might be associated with the presence of low synaptic levels of 5-HT in and pre-synaptic autoreceptors, ultimately limiting the increase in
regions of the CNS that modulate ejaculation, possibly because of 5-HT release into the synapse. Although chronic administration of
variations in 5-HT receptor sensitivity.
20
Thus, a physiological basis for PE SSRIs may produce a greater net elevation in 5-HT signalling by
might involve an underlying imbalance between 5-HT
1A
(hypersensitive preventing the increase in the 5-HT
1A
receptor-mediated
response) and 5-HT
2C
or 5-HT
1B
receptor activity (hyposensitive autoregulatory feedback loop in pre-synaptic neurones,
21
these
response),
21
although this hypothesis requires further investigation and chronic changes in signalling could also be responsible for some of
confirmation. Overall, based on the current neurochemical knowledge of the side effects associated with ongoing SSRI therapy.
14
ejaculation, it appears that increasing central 5-HT is a relevant
pharmacological strategy to delay ejaculation. Considering the shortcomings of chronic SSRI treatment, an optimal
therapy for PE would have a short duration of activity, with clinical
Pharmacological Management of efficacy after each dose for on-demand treatment and no need for
Premature Ejaculation lead-in dosing.
38
It is possible that on-demand administration of a
The management of PE is shifting from a traditional diagnostic and short-acting SSRI with a sufficiently rapid onset of action could
treatment pattern based on expert opinion to a more experimental, provide an immediate increase in synaptic 5-HT levels, thus
evidence-based approach.
22–24
Clinical outcome data using precise overwhelming synaptic feedback control mechanisms (i.e. 5-HT
end-points are the cornerstone of evidence-based medicine, but autoreceptor activation) or transporter trafficking, and producing a
until recently such evidence was limited in PE. Measurement of the clinically meaningful effect without the need for continuous
intravaginal ejaculatory latency time (IELT) may provide the most administration. Furthermore, an agent that is rapidly cleared could
objective and quantitative method for assessing the severity and minimise unnecessary drug exposure when administered on demand,
EUROPEAN UROLOGICAL REVIEW
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