Cruz_EU_Genito.qxp 25/2/08 11:42 am Page 44
overactivity. Very recently, a placebo-controlled trial showed that an Intracellular pathways have shown interesting potential for OAB
NK1 receptor antagonist was slightly superior to placebo in decreasing treatment. Rho-kinase pathways enable bladder smooth muscle cells to
urgency, urgency incontinence and frequency.
contract under intense noradrenaline stimulation. Spontaneous
hypertensive rats have an excess of sympathetic drive and exhibit
Nerve growth factor (NGF) neutralisation or the blockade of high- bladder hyperactivity. The latter can be controlled by Rho-kinase
affinity NGF receptors TrkA and p75 became attractive targets for OAB inhibitors.
The mitogen-activated protein kinase (MAPK) pathway is a
treatment recently. The urine of OAB patients contains 10 times more ubiquitous group of kinases. They are overexpressed in the spinal cord
NGF than normal age-matched individuals.
Animal experiments had of OAB rat models.
Interestingly, inhibition of MAPK pathway
shown that NGF increases bladder reflex activity.
decreased bladder overactivity while it had no effect on the bladder
function of naïve rats.
A variety of potassium ion (K
) channels have been reported to
regulate the contractility of urinary bladder.
openers also showed serious problems of cardiac toxicity. New K
OAB patients have poor QoL
and less productivity at work.
channel openers have been specifically designed to avoid cardiac number of patients requesting treatment is increasing steeply, thereby
adverse effects, but it is unclear whether they maintain, untouched, increasing the burden of OAB on the health budget of developed
the capacity to influence bladder function. countries.
Thus, highly effective drugs for the treatment of this
bothersome disease are necessary. At the moment, antimuscarinic drugs
Purinergic receptors have drawn attention as potential targets for OAB remain the first pharmacological option, whereas botulinum toxin may
treatment after the demonstration that P2X3 knockout mice had be better used in refractory cases. Nevertheless, the intense research
fewer bladder reflex contractions than their wild-type littermates.
going on in this field is expected to quickly increase the pharmacological
However, effective P2X3 antagonists are not yet available. alternatives and eventually provide the cure for OAB. ■
1. Abrams P, Cardozo L, Fall M, et al., The standardisation 14. Chui M, Williamson T, Arciniega J, et al., Patient persistency resiniferatoxin in patients with idiopathic detrusor instability
of terminology of lower urinary tract function: report with medications for overactive bladder, Value Health, suggests that involuntary detrusor contractions are triggered
from the Standardisation Sub-Committee of the International 2004;7:366. by C-fiber input, J Urol, 2002;168:575–9.
Continence Society, Neurourol Urodyn, 2002;21: 15. Chapple C, Khullar V, Gabriel Z, et al., The effects of 28. Kuo HC, Liu HT, Yang WC, Therapeutic effect of multiple
167–78. antimuscarinic treatments in overactive bladder: a systematic resiniferatoxin intravesical instillations in patients with
2. Irwin DE, Milsom I, Hunskaar S, et al., Population-Based review and meta-analysis, Eur Urol, 2005;48:5–26. refractory detrusor overactivity: a randomized, double-blind,
Survey of Urinary Incontinence, Overactive Bladder, and Other 16. Chapple CR, Martinez-Garcia R, Selvaggi L, et al., A placebo controlled study, J Urol, 2006;176:641–5.
Lower Urinary Tract Symptoms in Five Countries: Results of comparison of the efficacy and tolerability of solifenacin 29. Levin RM, Ruggeri MR, Wein AJ, Identification of receptor
the EPIC Study, Eur Urol, 2006;50:1306–15. succinate and extended release tolterodine at treating subtypes in the rabbit and human urinary bladder by selective
3. Kelleher CJ, Cardozo LD, Khullar V, et al., A medium-term overactive bladder syndrome: results of the STAR trial, Eur radio-ligand binding, J Urol, 1988;139:844–8.
analysis of the subjective efficacy of treatment for women Urol, 2005;48:464–70. 30. Smet PJ, Moore KH, Jonavicius J, Distribution and
with detrusor instability and low bladder compliance, Br J 17. Chapple C, Steers W, Norton P, et al., A pooled analysis of colocalization of calcitonin gene-related peptide tachykinins
Obstet Gynaecol, 1997;104:988–93. three phase III studies to investigate the efficacy, tolerability and vasoactive intestinal peptide in normal and idiopathic
4. Halaska M, Ralph G, Wiedemann A, et al., Controlled, and safety of darifenacin, a muscarinic M3 selective receptor unstable human urinary bladder, Lab Invest, 1997;77:37–49.
double-blind, multicentre clinical trial to investigate long-term antagonist, in the treatment of overactive bladder, BJU Int, 31. Green S, Bergner D, Kaufman J, et al., A pilot study to assess
tolerability and efficacy of trospium chloride in patients with 2005;95:993–1001. the effect of treatment with an NK-1 receptor antagonist on
detrusor instability World J Urol, 2003;20:392–9. 18. Chapple C, Van Kerrebroeck P, Tubaro A, et al., Efficacy of urge urinary incontinence symptoms, Neurourol Urodyn,
5. Anderson RU, Mobley D, Blank B, et al., Once daily controlled fesoterodine in patients with overactive bladder: 2006;25:619–20, abstract 91.
versus immediate release oxybutynin chloride for urge urinary improvements in OAB symptoms and health-related quality of 32. Kim JC, Park EY, Seo SI, et al., Nerve growth factor and
incontinence OROS Oxybutynin Study Group, J Urol, life, Eur Urol, 2007;6:274, abstract. prostaglandins in the urine of female patients with overactive
1999;161:1809–12. 19. Kaplan SA, Walmsley K, Te AE, Tolterodine extended release bladder, J Urol, 2006;175:1773–6.
6. Gleason DM, Susset J, White C, et al., Evaluation of a new attenuates lower urinary tract symptoms in men with benign 33. Lamb K, Gebhart GF, Bielefeldt K, Increased nerve growth
once-daily formulation of oxbutynin for the treatment of prostatic hyperplasia, J Urol, 2005;174: 2273–5. factor expression triggers bladder overactivity, J Pain,
urinary urge incontinence, Ditropan XL Study Group, Urology, 20. Abrams P, Kaplan S, De Koning Gans HJ, et al., Safety and 2004;5:150–56.
1999;54:420–23. tolerability of tolterodine for the treatment of overactive 34. Gopalakrishnan M, Shieh CC, Potassium channel subtypes as
7. Diokno A, Sand P, Labasky R, et al., Long-term safety of bladder in men with bladder outlet obstruction, J Urol, molecular targets for overactive bladder and other urological
extended-release oxybutynin chloride in a community-dwelling 2006;175: 999–1004. disorders, Expert Opin Ther Targets, 2004;8:437–58.
population of participants with overactive bladder: a one-year 21. Kaplan SA, Roehrborn CG, Rovner ES, et al., Tolterodine and 35. Cockayne DA, Hamilton SG, Zhu QM, et al., Urinary bladder
study, Int Urol Nephrol, 2002;34:43–9. tamsulosin for treatment of men with lower urinary tract hyporreflexia and reduced pain-related behaviour in P2X3-
8. Abrams P, Malone-Lee J, Jacquetin B, et al., Twelve-month symptoms and overactive bladder: a randomized controlled deficient mice, Nature, 2000;407:1011–15.
treatment of overactive bladder: efficacy and tolerability of trial, JAMA, 2006;296:2319–28. 36. Rajasekaran M, Wilkes N, Kuntz SE, et al., Rho-kinase
tolterodine, Drugs Aging, 2001;18:551–60. 22. Popat R, Apostolidis A, Kalsi V, et al., A comparison between inhibition suppresses bladder hyperactivity in spontaneously
9. Kreder K, Mayne C, Jonas U, Long-term safety, tolerability and the response of patients with idiopathic detrusor overactivity hypertensive rats, Neurourol Urodyn, 2005;24:295–300.
efficacy of extended-release tolterodine in the treatment of and neurogenic detrusor overactivity to the first intradetrusor 37. Cruz CD, Avelino A, McMahon SB, et al., Increased spinal
overactive bladder, Eur Urol, 2002;41:588–95. injection of botulinum-A toxin, J Urol, 2005;174:984–9. cord phosphorylation of extracellular signal-regulated kinases
10. Van Kerrebroeck P, Kreder K, Jonas U, et al., Tolterodine 23. Schmid DM, Sauermann P, Werner M, et al., Experience with mediates micturition overactivity in rats with chronic bladder
once-daily: superior efficacy and tolerability in the treatment 100 cases treated with botulinum-A toxin injections in the inflammation, Eur J Neurosci, 2005;21:773–81.
of the overactive bladder, Urology, 2001;57:414–21. detrusor muscle for idiopathic overactive bladder syndrome 38. Cruz CD, McMahon SB, Cruz F, Spinal ERK activation
11. Chapple CR, Rechberger T, Al-Shukri S, et al., Randomized, refractory to anticholinergics, J Urol, 2006;176:177–85. contributes to the regulation of bladder function in spinal cord
double-blind placebo- and tolterodine-controlled trial of the 24. Kuo HC, Urodynamic evidence of effectiveness of botulinum A injured rats, Exp Neurol, 2006;200:66–73.
once-daily antimuscarinic agent solifenacin in patients with toxin injection in treatment of detrusor overactivity refractory 39. McGhan WF, Cost effectiveness and quality of life
symptomatic overactive bladder, BJU Int, 2004;93:303–10. to anticholinergic agents, Urology, 2004;63:868–72. considerations in the treatment of patients with overactive
12. Kelleher CJ, Cardozo L, Chapple CR, et al., Improved quality 25. Kuo HC, Clinical effects of suburothelial injection of botulinum bladder, Am J Manag Care, 2001;7:S62–S75.
of life in patients with overactive bladder symptoms treated A toxin on patients with nonneurogenic detrusor overactivity 40. Irwin DE, Milsom I, Kopp Z, et al., Impact of overactive
with solifenacin, BJU Int, 2005;95:81–5. refractory to anticholinergics, Urology, 2005;66:94–8. bladder symptoms on employment, social interactions and
13. Haab F, Cardozo L, Chapple CR, et al., Long-term open-label 26. Charrua A, Cruz C, Cruz F, et al., TRPV1 is essential for the emotional well-being in six European countries, BJU Int,
solifenacin treatment associated with persistence with therapy generation of noxious bladder input and bladder overactivity 2006;97:96–100.
in patients with overactive bladder syndrome, Eur Urol, 2005; in cystitis, J Urol, 2007;177:1537–41. 41. Wagner TH, Hu TW, Economic costs of urinary incontinence in
47:376–84. 27. Silva C, Ribeiro MJ, Cruz F, The effect of intravesical 1995, Urology, 1998;51:355–61.
44 EUROPEAN GENITO-URINARY DISEASE 2007