Chemistry Reference
In-Depth Information
over the dopamine (DA) reuptake transporter (DRI) would be desirable to
avoid any dopaminergic effects.
In the context of treating SUI, SNRIs are believed to work by blocking
reuptake of 5-HT and NA in Onuf's nucleus in the sacral spinal cord.
16
Pudendal motor neurons located in Onuf's nucleus regulate the urethral striated
muscle sphincter and Onuf's nucleus has a high density of 5-HT and NA
receptors.
16
Furthermore, it has been reported that the prevention of urine
leakage could be mediated by stimulation of central 5-HT
2
and a
1
adrenergic
receptors, resulting in more effective closure of the urethral sphincter.
19
In
addition, comparison of the effects of an SRI, an NRI, co-administration of an
SRI with an NRI, and a dual SNRI in lower urinary tract function in cats has
shown that improving bladder storage is unique to the dual SNRI mechanism.
20
12.1.3 Compounds in Class
There are currently four SNRIs approved for clinical use. Venlafaxine is an
orally active, selective dual SNRI developed and launched by Wyeth for the
treatment of depression.
6
Venlafaxine was launched in 1994 as Effexor
t
as ''first
in class'' of the second-generation of antidepressants with dual SNRI activity
and has a much improved side-effect profile compared with the classical tricyclic
antidepressants. In a recent small clinical study, venlafaxine has shown potential
utility as a treatment for SUI.
21
In 2008, Wyeth then launched desvenlafaxine
(Pristiq
t
) for the treatment of major depressive disorder (MDD). Desvenla-
faxine is the major active metabolite of venlafaxine and offers a reduced risk of
drug-drug interactions as a potential advantage over other SNRIs.
10
Milnaci-
pran is also a dual SNRI and was introduced in Europe by Pierre Fabre in 1997
as Ixel
t
. Milnacipran is approved for the treatment of depression
7
and is cur-
rently in phase 3 trials for the treatment of fibromyalgia.
22
Duloxetine was first launched in the US in 2004 as Cymbalta
t
by Eli Lilly
for the treatment of major depressive disorder, generalised anxiety disorder and
diabetic peripheral neuropathic pain.
8
Duloxetine has also been approved for
the treatment of SUI in Europe and is marketed as Yentreve
t
.
5,14,16,19
(
þ
)-(S)-
Duloxetine is a combined SNRI with potent inhibitory activity at both the
human 5-HT (K
i
¼
0.8 nM) and NA (K
i
¼
7.5 nM) transporters.
23
Duloxetine
weakly inhibits DA reuptake (K
i
¼
240 nM) with no significant activity at
aminergic receptors (M, H
1
, a
1
, a
2
, D).
24
Further pharmacological evaluation
in vivo, in microdialysis experiments, showed that duloxetine dose-dependently
increased extracellular 5-HT and NA levels in interstitial fluid of the frontal
cortex and hypothalamus of conscious rats.
24
Duloxetine is well absorbed after
oral administration, with bioavailability of 32-80% and a mean plasma half-
life of 12 h, consistent with the recommendation of a twice-daily dosing regime.
The primary route of duloxetine clearance is through hepatic oxidative meta-
bolism to a number of metabolites and in vitro studies have shown that
duloxetine is predominantly metabolised by the enzymes CYP1A2 and
CYP2D6. Duloxetine plasma exposure is increased 3- to 6-fold when co-dosed
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