| Reference | 1. Eur J Heart Fail. 2009 Aug;11(8):771-8. doi: 10.1093/eurjhf/hfp087. Epub 2009 Jun
30.
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Effect of piboserod, a 5-HT4 serotonin receptor antagonist, on left ventricular
function in patients with symptomatic heart failure.
<br>
Kjekshus JK(1), Torp-Pedersen C, Gullestad L, Køber L, Edvardsen T, Olsen IC,
Sjaastad I, Qvigstad E, Skomedal T, Osnes JB, Levy FO.
<br>
Author information: <br>
(1)Department of Cardiology, Oslo University Hospital, Rikshospitalet,
Sognsvannsveien 20, Oslo, Norway. [email protected]
<br>
AIMS: Myocardial 5-HT(4) serotonin (5-HT) receptors are increased and activated
in heart failure (HF). Blockade of 5-HT(4) receptors reduced left ventricular
(LV) remodelling in HF rats. We evaluated the effect of piboserod, a potent,
selective, 5-HT(4) serotonin receptor antagonist, on LV function in patients with
HF.<br>
METHODS AND RESULTS: This was a prospective, double-blind, parallel group trial
in patients with NYHA class II-IV HF and LV ejection fraction (EF) < or =0.35.
Patients receiving standard HF treatment were randomized to placebo (n = 70) or
piboserod 80 mg (n = 67) for 24 weeks including 4 weeks up titration. The primary
endpoint was LVEF measured by cardiac magnetic resonance imaging (MRI). Secondary
endpoints were LV volumes, N-terminal pro-brain natriuretic peptide,
norepinephrine, quality of life, and 6 min walk test. Piboserod significantly
increased LVEF by 1.7% vs. placebo (CI 0.3, 3.2, P = 0.020), primarily through
reduced end-systolic volume from 165 to 158 mL (P = 0.060). There was a trend for
greater increase in LVEF (2.7%, CI -1.1, 6.6, P = 0.15) in a small subset of
patients not on chronic beta-blocker therapy. There was no significant effect on
neurohormones, quality of life, or exercise tolerance. Patients on piboserod
reported more adverse events, but numbers were too small to identify specific
safety issues.<br>
CONCLUSION: Although patients with chronic HF had a small but significant
improvement in LVEF when treated with piboserod for 24 weeks, the result was not
reflected in significant changes in other efficacy parameters, and its clinical
relevance remains uncertain.
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2. World J Urol. 2005 Jun;23(2):147-51. Epub 2005 May 18.
<br>
Piboserod (SB 207266), a selective 5-HT4 receptor antagonist, reduces serotonin
potentiation of neurally-mediated contractile responses of human detrusor muscle.
<br>
Darblade B(1), Behr-Roussel D, Gorny D, Lebret T, Benoit G, Hieble JP, Brooks D,
Alexandre L, Giuliano F.
<br>
Author information: <br>
(1)Pelvipharm, Domaine CNRS, 1 avenue de la terrasse, Bâtiment 5, 91190
Gif-sur-Yvette, France.
<br>
The aim of this study is to evaluate the potency of piboserod (SB 207266), a
selective 5-HT(4) receptor antagonist, at inhibiting the 5-HT(4)-mediated
potentiating effect of serotonin (5-HT) on the neurally-mediated contractile
responses of human detrusor strips to electrical field stimulations (EFS). Strips
of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting
tension of 500 mg and EFS (20 Hz, 1 ms duration at 300 mA for 5 s) was applied
continuously at 1 min intervals. After stabilization of the EFS-induced
contractions, concentration-response curves to 5-HT (0.1 nM-100 microM) were
constructed in the absence or presence of 1 or 100 nM of piboserod. The
experiments were performed in the presence of methysergide (1 microM) and
ondansetron (3 microM) to block 5HT(1)/5HT(2) and 5-HT(3) receptors,
respectively. 5-HT potentiated the contractile responses to EFS of human bladder
strips in a concentration-dependent manner, with a maximum mean of 60.0+/-19.9%
of the basal EFS-evoked contractions. Piboserod did not modify the basal
contractions but concentration-dependently antagonized the ability of 5-HT to
enhance bladder strip contractions to EFS. In presence of 1 and 100 nM of
piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0+/-7.9 and
38.7+/-8.7%, respectively. A mean apparent antagonist dissociation constant value
(K(B)) of 0.56+/-0.09 nM was determined. These data show the ability of piboserod
to antagonize with high potency the enhancing properties of 5-HT on
neurally-mediated contractions of isolated human bladder strips. Therefore, the
5-HT(4) receptor might represent an attractive pharmacological target for the
treatment of overactive bladder.
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