Biology Reference
In-Depth Information
for 12 weeks. Primary endpoints with regard to the LUT symptomatology were
changes from baseline in IPSS, maximum urinary flow rate (Q max ), medium urinary
flow rate (Q ave ), and postvoid residual urine (PVRU) volume. Improvement in IPSS
was significant in all treatments arms, but most pronounced with the drug combina-
tions. PVRU, Q max , frequency, and nocturia were significantly improved with
alfuzosin only and the combination regimen. From the results, demonstrating the
significant improvement in uroflowmetry measures and IPSS, it was concluded that
combined therapy is more effective than monotherapy with either agent to improve
voiding dysfunction in men with LUTS suggestive of BPH (Kaplan et al. 2007 ;
Liguori et al. 2009 ). Combining a PDE5 inhibitor with a 5-alpha-reductase inhibitor
(5-ARI, such as dutasteride or finasteride) or an antimuscarinic drug (such as
darifenacin, fesoterodine, oxybutinin, or tolterodine) has also been suggested as a
potential treatment for LUTS. However, to date, no clinical evidence has been
presented indicating that such treatment regimens are effective and safe in the
individual patient (Andersson 2008 ).
7 Bladder Overactivity
Anticholinergic drugs are currently the therapy of choice to treat urgency and urge
incontinence (Andersson et al. 2001 ). Nevertheless, to date, muscarinic receptor
blockers that act exclusively on detrusor smooth muscle are not available. Moreover,
the unstable detrusor seems to be regulated in part by noncholinergic mechanisms.
These factors may explain the common side effects and limited clinical efficacy of
anticholinergic medications. The specific modulation of intracellular second mes-
senger pathways may offer a promising possibility to achieve selective modulation
of tissue function, especially with regard to the contraction and relaxation of human
urinary bladder smooth musculature. Using chromatographic methods, Truss et al.
( 1996a ) were the first who reported the spectrum of PDEs in the human detrusor;
these include PDE1 (cAMP/cGMP-PDE, Ca 2+ /calmodulin-dependent), PDE2
(cAMP-PDE, cGMP-dependent), PDE3 (cAMP-PDE, cGMP-inhibited), PDE4
(cAMP-PDE), and PDE5 (cGMP-PDE). They also demonstrated relaxant responses
of isolated human detrusor strip preparations contracted by the muscarinic agonist
carbachol to the nonspecific PDE inhibitor papaverine and the PDE1 inhibitor
vinpocetine. The relaxing effects of the drugs were paralleled by an increase in
tissue levels of cAMP and cGMP. They concluded from their findings that the
cAMP-pathway and PDE1 might be of functional significance in the control of
detrusor smooth muscle contractility (Truss et al. 1996b ). The predominant expres-
sion of PDE1 in the human detrusor was later confirmed by RT-PCR analysis
(Uckert et al. 2009 ). Results from a randomized, double-blind, placebo-controlled
study to assess effects of the PDE1 inhibitor vinpocetine in patients with urgency
and urge incontinence, who had failed standard pharmacological therapy, demon-
strated that vinpocetine was superior to placebo with regard to the clinical outcome
parameters micturition frequency, bladder volume at first sensation, bladder
Search WWH ::




Custom Search