The Challenge of Overactive Bladder Therapy: Alternative to Antimuscarinic Agents

Review Article Overactive Bladder Therapy International Braz J Urol Vol. 32 (6): 620-630, November - December, 2006

Massimo Lazzeri, Michele Spinelli

Department of Urology (ML), Casa di Cura Santa Chiara Firenze, and Department of Neurourology (MS), Spinal Unit Ospedale Ca’ Grande, Niguarda, Milan, Italy

ABSTRACT

Contemporary, the management of overactive bladder (OAB), a medical condition characterized by urgency, with or without urge urinary incontinence, frequency and nocturia, in absence of genitourinary pathologies or metabolic factors that could explain these symptoms, is complex, and a wide range of conservative treatments has been offered, including bladder training, biofeedback, behavioral changes, oral or intravesical anticholinergic agents, S3 sacral neuromodulation and peripheral electrical stimulation. Clinical efficacy of these treatments remains an open issue and several experimental and clinical studies were carried out in the last years improving the results of medical treatment. Here we review the pathophysiology of micturition reflex, the current therapies for OAB and the rationale for alternative treatments. Furthermore we critically address the potential use of medications targeting the central nervous system (CNS) and the primary sensory nerves of the bladder wall, we review the use of agonists of nociceptin/orphanin protein (NOP) receptor and finally we report the results obtained by intradetrusor injection of botulinum toxin.

Key words: overactive bladder; voiding dysfunction; pharmacotherapy; receptor, orphanin fq; botulinum toxins Int Braz J Urol. 2006; 32: 620-30

INTRODUCTION been reported also for United State of America where around one sixth of adults aged 18 years and over have Overactive bladder (OAB) is a medical con- symptoms of OAB; the estimated prevalence is 33 dition characterized by urgency, with or without urge million US residents aged over 18 years (3). Recently urinary incontinence, frequency and nocturia, in ab- Erwin reported a cross-sectional population-based sur- sence of genitourinary pathologies or metabolic fac- vey of people > 18 years showing that the total preva- tors that could explain these symptoms (1). This defi- lence in 4 European countries is 12.2% and confirmed nition represents an important clinical message because that OAB is a common condition in men and women in the era of High-Tech medicine, people look for medi- across all adult age group (4). One third of people with cal help in the same way as in the past as a result of overactive bladder have urge urinary incontinence and symptoms. The key symptom, which characterizes large population studies have reported that the preva- OAB, is “urgency”: the sudden and compelling desire lence of symptoms of OAB increases with age (5). to pass urine, which is difficult to defer. The aim of this paper is to address critically OAB affects one sixth of European popula- the therapy of OAB providing an up-to-dated insight tion aged 40 years or over (2) and similar data have on alternative strategies to antimuscarinics.

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PATHOPHYSIOLOGY OF MICTURITION sympathetic system also provides an excitatory in- REFLEX put to the urethra smooth muscle by the postganglionic nerve terminal release of norepinephrine (NA) α The lower urinary tract serves two main func- which excites 1 receptors in the urethra leading to tions: the storage of urine without leakage (storage the urethral closure. The somatic system provides phase) and the periodic release of urine (voiding an excitatory input to the striated urethral muscle; phase). During the storage phase the detrusor muscle in this case the motoneurons are located along the is relaxed and the outlet region is contracted to main- lateral border of the ventral horn of the sacral spinal tain continence. During the voiding phase the detru- cord, which is known as the Onuf’s nucleus. They sor muscle contracts and the outlet region relaxes fa- release Ach, which acts on nicotinic receptors to cilitating bladder emptying. These two functions are induce muscle contraction. dependent on central, peripheral autonomic and so- Immunohistochemical and morphological matic neuronal pathways and local peripheral factors. studies, which have been conducted on the bladder During the storage phase the afferent impulses reach wall, showed that there are a lot of neuronal terminal the central nervous system (CNS) from the lower uri- endings that do not correspond to cholinergic and nary tract and afferent activity sends information to adrenergic innervations (11). These nerves, which are the periaqueductal grey of pons. In the pontine teg- non adrenergic - non cholinergic (NANC), are pep- mentum there are two regions: a medially located one tide containing fibers and they are selectively sensi- (M-region), which corresponds to Barrington’s tive to capsaicin, the pungent ingredient of red pep- nucleus or pontine micturition center which is respon- pers, heat and H+. They are primary afferents and may sible of coordination of micturition reflex (6), and a play an important role in the regulation of lower uri- laterally located one (L-region), which is involved in nary tract functions (12). These nerves consist of small the storage phase suppressing the bladder contrac- myelinated Aδ and un-myelinated C fibers, which are, tion and improving external sphincter muscle activ- however, “silent” under normal conditions. ity during this phase (7). The emerging development Data from several laboratories have recently of functional imaging such as single photon emission shown the importance of peripheral local factors in tomography (SPET), positron emission tomography the regulation of micturition reflex. The bladder (PET) and functional MRI showed several urothelium can respond to chemical and mechanical sovraspinal-sovrapontine (cortical) areas involved in stimuli releasing different mediators, which target the the micturition reflex, but so far their specific role receptors of adjacent sensory nerves (13). Birder in- remains obscure (8-10). troduced the concept of “neuron-like properties” of Three different sets of peripheral neuronal urothelium. Urothelium responds to stretch, during systems are involved in the micturition reflex: the the filling phase of micturition reflex, by increasing parasympathetic system the sympathetic system and the size of apical umbrella cells and by releasing the somatic system. The parasympathetic system mediators, which activate sensory fibers (14). Finally originates in the sacral level of the spinal cord (S2- several investigators suggest a regulatory role for in-

S4) and provides an excitatory input to the bladder terstitial cells, which are part of a “vesical module” by the postganglionic nerve terminal release of Ace- consisting of nerves, smooth muscle cells and inter- tylcholine (Ach), which excites muscarinic recep- stitial cells. It is thought that this module may receive tors (M2, M3) in the detrusor smooth muscle leading diverse inputs and may be able to modulate local re- to the bladder contraction. The sympathetic system flex or activity (15). originates in the thoracolumbar cord (Th11-L2) and OAB may result from increased bladder af- provides an inhibitory input to the bladder by the ferent activity, decreased capacity to handle afferent postganglionic nerve terminal release of norepineph- information or decreased suprapontine inhibition in β rine (NA) which excites 3 receptors in the body of the CNS, and increased peripheral sensibility to re- the detrusor leading to the bladder relaxation. The lease mediating transmitters. This last situation,

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known as “bladder oversensitivity”, could originate preconceived notion about anticholinergics. Chapple from the release of neurotransmitters by urothelium et al. carried out a systematic review and a meta-analy- or sensitization of sensory nerves by paracrine path- sis on the effects of antimuscarinic in the OAB therapy ways. The CNS as well as the periphery may repre- (18). His review was planned to assess the safety, tol- sent the target for a new class of medications against erability and efficacy of antimuscarinic in the OAB OAB. therapy, considering the effects on quality of life (QoL), differences between different antimuscarinics and, finally, addressing criticism of Herbison’s review. CURRENT THERAPIES FOR Chapple’s review has many differences regarding OVERACTIVE BLADDER Herbison’s study. He did a systematic analysis of QoL data, a differentiation between individual Anticholinergics, which antagonist Ach for antimuscarinics, including active controlled trials and the muscarinic receptors, are first line pharmacologi- following a “splitting” approach and not a “cumula- cal treatment for overactive bladder. The indication tive” approach. Chapple et al. reported that for the treatment of OAB derives from a high level of antimuscarinic formulations, apart from Oxybutynin evidence (Level-1) and high grade of recommenda- IR (immediate release) were found well tolerated and tion (Grade-1) (16). Anticholinergics produce signifi- no drug was associated with a significant risk of death. cant symptom improvements in OAB syndromes Also, in this review dry mouth was the most com- when they are compared to a placebo and the number monly reported adverse effect, even if other adverse of anticholinergic drugs available on the market is reactions were included (blurred vision, constipation, increasing. However, the debate about the patho- dyspepsia, nausea, vomiting, urinary retention). physiological rationale and the clinical use of Antimuscarinics were able to reduce frequency, ur- antimuscarinic agents remains an unsolved issue. gency episodes by over one episode per day, inconti- Herbison reported a systematic review of nence by half an episode or more per day and the anticholinergic drug treatment compared to a placebo volume voided per micturition was increased. Finally therapy in the treatment of overactive bladder as a patients receiving antimuscarinics have greater im- result from randomized controlled trials (17). He provements in QoL than patients on placebo arm. found that those patients receiving active treatment Chapple et al. (18) concluded that there is a quantifi- were more likely to be subjectively improved and they able objective and clinical benefit conferred by had about one leakage episode less in 48 hours than antimuscarinics in the therapy of OAB. those taking placebo. Urodynamic assessment showed However, most of the studies, which were larger increase in maximum cystometric capacity in considered in the review, had limitations of evidences those receiving active treatment and the volume at such as choice of outcome measure, trial length, re- first contraction increased more in the drug group than stricted population, the high placebo effect and eco- in the placebo group. Dry mouth was the most fre- nomic issues. For all these reasons, today, many of us quently reported side effect. Herbison concluded that are disputing formally and systematically in order to although statistically significant, the differences be- trigger an appropriate response to the question on the tween anticholinergic drugs and placebo were small, rational of use of anticholinergics and for finding al- apart from the increased rate of dry mouth in patients ternative therapies. receiving active treatment. For many of the outcomes studied, the observed difference between anticholinergics and placebo may be of questionable clinical RATIONALE FOR ALTERNATIVE significance. THERAPIES TO ANTICHOLINERGICS After the publication of this paper many urologists felt that Herbison had inappropriately writ- In the past, many factors discouraged the ex- ten off this class of drugs and that the author had a tensive research on new drugs in the treatment of OAB

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α or LUTS. The main limitations were due to the com- that i.t. or i.c.v. 1 antagonists reduced the detrusor plex neuropharmacological arrangement of voiding overactivity in the spontaneously hypertensive rat, i.t. reflex and sexual function, the simple “easy to ac- or i.c.v. tamsulosine inhibits the micturition reflex by α cept” idea of antagonistic, parasympathetic cholin- the activation of spinal receptors and 2 agonists pro- ergic and sympathetic adrenergic control of the LUT duce the activation of micturition reflex by the acti- α and the complex interrelationship between the vol- vation of supraspinal and spinal receptors (25). 1A-, α α untary somatic control of visceral reflex and the in- 1B-, and 1D-AR mRNA can be demonstrated in the voluntary components. parasympathetic nucleus in the sacral spinal cord (26) α In the last 2 decades the neuropharmacol- and 1d-AR KO mice vs. wild type controls showed ogy gained advantages from basic science research lower voiding frequency, larger bladder capacity and and the experimental results were translated in the larger voided volumes (27). Naftopidil and tamsulosin clinical practice. The main advantages were due to both block α-ARs in prostatic smooth muscle, and the discovery of non-adrenergic - non-cholinergic both agents (especially naftopidil) may also act on innervation (NANC) of the LUT (19), the recogni- the lumbosacral cord (28). It is interesting report that tion of a multiplicity of neurotransmitters (monoam- tamsulosin and aftopidil in a 8-week crossover-study ines, purines, amino acid, peptides and nitric oxide) on 96 BPH patients decreased the I-PSS for storage (11), the concept of co-transmission (nerves release symptoms (29). This study suggests that naftopidil is more than one transmitter) and the recognition of as effective and safe as tamsulosin and both drugs the basilar importance of a sub set of sensory nerves were effective in improving storage and voiding symp- which are sensible to capsaicin, the pungent ingre- toms. However, there was no difference in clinical α dient of red chilli, in the control of micturition re- efficacy or adverse effects between the 1 AR antago- α α flex (20). Finally, the discovery of a new variety of nists with different affinity to 1 subtypes, 1A and α different receptors, involved in the regulation of 1D (30). sensory nerves’ conduction and changes occurring There has been little interest in developing during not only development and ageing but also drugs active on opioid mechanisms for the treatment after trauma or chronic inflammation of bladder disorders, despite the profound inhibitory (neuroplasticity), were basilar for the development effects that morphine and analogs have on the mictu- of alternative therapies (21-23). rition reflex. However, tramadol, which is both a µ- Today CNS, sensory nerves and bladder receptor agonist and an inhibitor of noradrenaline and smooth muscle cells represents the main targets of serotonin uptake, has been reported to have promis- alternative strategy for OAB. ing effects on micturition in animal models (31). Tramadol produced the inhibition of detrusor overactivity induced by cerebral infarction in rats and CENTRAL NERVOUS SYSTEM the inhibition of detrusor overactivity induced by apomorphine in rats (32). Several CNS transmitters/receptors systems, Serotonin and its receptors may play an im- including adrenoceptors, γ-aminobutyric acid portant role in the central regulation of micturition (GABA), opioid, serotonin, noradrenaline, dopamine, reflex. Exposure to selective serotonin reuptake in- and glutamatergic receptors are known to be involved hibitors (SSRIs) is associated with an increased risk in micturition control (24). (15/1000 patients) for developing urinary inconti- Several and different adrenoceptors have nence especially between the elderly and users of been found in the brain and spinal cord. High levels sertraline are at the highest risk (33). Clomipramine α of 1A mRNA have been showed in many hypotha- treated female rat pups void more frequently than α α lamic nuclei, 1A mRNA and 1B mRNA in amygdala controls, have a lower bladder capacity and show α and raphe nuclei and 1D mRNA in the cortex, hip- detrusor overactivity. Fluoxetine treatment reverses pocampus and amygdala. Different studies showed these effects. Up to date, no convincing documenta-

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tion exists whether or not SSRIs are effective in the cin targets the transient receptor potential vanilloid- treatment of OAB, and despite positive acute effects 1 (TRPV1), which is expressed on small-to-medium in preclinical models, there are no proof of concept size afferent neurons, which are most of C-type but studies showing that subtype selective 5-HT receptor also in a fraction of A-δ type. The acute exposure to antagonists (5-HT1A, 5-HT7) are effective in the capsaicin depolarizes and excites sensory fibers ex- OAB treatment. pressing TRPV1 receptors. This excitation is followed In the normal rat, stimulation of GABA recep- by a refractory period. It means that the repeated, long- tors, mainly in the central nervous system, inhibits term, high dose exposure to capsaicin desensitizes, micturition. Antagonism of GABAB receptors stimu- defunctionalizes and ultimately damages peripheral lates micturition, suggesting that the receptors are terminals, which become unresponsive. In other under tonic GABAergic influence. Intrathecally words, the mechanism of action by which capsaicin baclofen attenuates oxyhemoglobin induced detrusor works is a long lasting reversible suppression of sen- overactivity, suggesting that the inhibitory actions of sory nerve activity and it is dependent on dose, time

GABAB receptor agonists in the spinal cord may be of exposure and interval between consecutive instil- useful for controlling micturition disorders caused by lations. C-fiber activation in the urothelium and/or The proof of concept that an inhibitory modu- suburothelium (34). Recently experimental studies lation of urinary bladder afferent nerves could achieve have demonstrated the inhibitory effect of exogenous a therapeutic benefit in the treatment of bladder gamma-aminobutyric acid (GABA) on micturition. overactivity, was obtained through the intravesical Tigabine inhibits the micturition reflex in rat and its instillation of repeated low concentration doses or site of action, which may be central (35). single high concentration doses of capsaicin (20). The Finally, Kim reported the effects of first experiences were performed in patients with neu- gabapentin in 14 out of 31 patients with refractory rogenic detrusor overactivity. De Ridder reported that OAB. He found an improvement of clinical param- repeated instillations of intravesical capsaicin was eters with fewer side effects, gabapentin was gener- effective in approximately 80% of the patients with ally well tolerated, and it can be considered in se- bladder overactivity due to spinal cord disease and lected patients an alternative treatment to the beneficial effect lasted 3 to 5 years (36). At the antimuscarinics. end of the 1990s Lazzeri questioned the efficacy and In conclusion, several promising new prin- the safety of capsaicin for the management of detru- ciples have been recently investigated, but only few sor hyperreflexia (37) and Petersen demonstrated, in drugs have passed the stage of “proof” of concept. a placebo controlled crossover study, that intravesical treatment with capsaicin did not show beneficial effects on detrusor hyperreflexia and produced sig- SENSORY NERVES nificant reactive changes in the bladder mucosa (38). Lazzeri reported that 12.96% of patients had a sig- Recently, the idea of afferent blockade by nificant episode of autonomic dysreflexia during the targeting afferent nerves that control the micturition infusion, 35.18% presented rhythmic detrusor con- reflex has gained the trust of urologists as a potential tractions causing the leakage of urine and 96% of the alternative to current drug therapies. The emerging patients with incomplete spinal lesion and bladder concept is that it would be more desirable to prevent sensation reported a warm/burning/painful sensation the micturition reflex that initiates overactive blad- (39). de Seze, by Bordeaux group, found that the cap- der, instead of blocking the contraction of detrusor saicin side effects were due to alcohol (the vehicle), smooth muscle. The concept of a therapeutic approach which were used, sometimes, at the concentration of through the modulation of the afferent arm of the 30%. When capsaicin was diluted in glucidic acid, micturition reflex emerged when investigators stud- intravesical instillation was equally effective with ied the effect of capsaicin on sensory nerves. Capsai- fewer adverse events (40). Owing to the warm/burn-

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ing sensation/discomfort that capsaicin produced in Recently experimental and clinical evidence subjects with normal sensation and increasing the has showed that the inhibitory system nociceptin/ regulation of non licensed agents, the source of cap- orphanin (NO) FQ - nociceptin/orphanin protein saicin mostly having been chemical rather than phar- (NOP) receptor, may play an important role in the macological suppliers, was replaced by the pharma- modulation of micturition reflex. Nociceptin inhibits ceutically prepared resiniferatoxin (RTX). RTX, ob- the activity of TRPV1-expressing neurons at the pe- tained from a cactus species of the genus Euphorbia, ripheral level by the activation of a specific G-pro- Euphorbia resinifera, is an ultra potent capsaicin ana- tein coupled receptor named nociceptin orphan pep- logue to a thousand fold the selective C-fiber neuro- tide (NOP) receptor (49). In a pilot, uncontrolled toxicity of capsaicin for comparable pungency and study, the intravesical infusion of N/OFQ increased with fewer side effects. Against a strong scientific the bladder capacity in a selected group of patients background of its demonstrated mode of action in suffering from neurogenic detrusor overactivity, but animal models, the use of this agent therefore held not in normal subjects (50). These findings were rep- out the promise of an effective “de-afferenting” in- licated in a placebo-controlled randomized study sug- stillation with little discomfort. However , the reality gesting that NOP receptor agonists modulate the mic- to date has unfortunately been otherwise. Following turition reflex in humans and they could represent a early positive reports of its effectiveness in both neu- suitable alternative to the treatment of OAB to oral rogenic (41,42) and idiopathic detrusor overactivity antimuscarinics (51). (43) large scale placebo controlled multicentric clinical trials in Europe and the US were initiated to examine the efficacy of the agent in patients with neu- BOTULINUM TOXIN rogenic bladder. During the course of these studies it became apparent, to those involved in the trials, that Botulinum toxin (BTX) is a complex pro- many patients were not responding at all, which lead tein, produced by the anaerobic bacterium to a review of the study procedures and the recogni- Clostridium botulinum. Previously known only as a tion of the possible loss of active drug availability cause of a serious and often fatal paralysis acquired due to the adsorptive properties of RTX to plastic. through ingestion of contaminated food, the neuro- Immunohistochemical evidence showed that respond- muscular blocking effect of the toxin has been ers had a demonstrable reduction of nerve density of thought that might alleviate muscle spasm due to suburothelial innervations, with a parallel reduction excessive neural activity of central origin. Local in the expression of TRPV1 and P2X receptors (44,45) injections of BTX have been showed effective in of these nerves. the treatment of strabismus, essential ble- Other centers continued to examine the ef- pharospasm, and hemifacial spasm and further stud- ficacy of RTX in detrusor overactivity (46,47) and ies indicate that BTX injections also can provide because of the known effect of RTX on afferent useful symptomatic relief in a variety of other con- innervations, a study looked at its efficacy in conditions characterized by involuntary spasms of cer- ditions of bladder pain or interstitial cystitis (48). tain muscle groups, notably in focal or segmental Encouraged by positive finings, a pharmaceutical dystonia including spasmodic torticollis, company recently funded a large scale placebo con- oromandibular dystonia (orofacial dyskinesia, Meige trolled study using RTX to treat interstitial cysti- syndrome), and spasmodic dysphonia. Recently the tis. Unfortunately the reported benefits were no unlicensed use of toxin in the treatment of lower greater in the active treatment than the placebo urinary tract (LUT) conditions has been described. group and it therefore seems unlikely that a phar- (52). LUT disorders are characterized by detrusor maceutical preparation of RTX will continue to be sphincter dyssynergia (53,54), detrusor overactivity made available unless there is some further devel- neurogenic detrusor overactivity (NDO) (55) and opment in this field. also idiopathic detrusor overactivity (IDO).

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Botulinum toxin is thought to work by cleav- efficiency. Voiding difficulty was reported by 75% ing a synaptosome-associated protein, SNAP-25, of patients, and 30% required catheterization. This thereby blocking the presynaptic release of acetyl- suggests that blockade of detrusor contractility choline at the neuromuscular junction. This protein through sub-urothelial sensory fibers was much more is part of SNARE complex, which is vital for vesicu- pronounced than at neuromuscular junctions or that lar exocytosis and relies of Ach. It is important to only a small amount of diffusion of BTX from the remind that, after exposure to botulinum toxin, neu- detrusor to the sub-urothelium occurs following de- ronal death does not occur, but the phenomenon of trusor injection. More recently Schulte-Baukloh re-sprouting of axons, leading to new synaptic con- performed BTX injections in patients with refrac- tacts, also occurs and these presumably account for tory OAB symptoms but with no evidence of DO on the return to muscular function, which is observed prior urodynamics (62). Significant improvements after a number of months (56). The re-sprouting of were seen in symptoms scores, bladder diary and axons might also play a role in hyperactivity of mus- urodynamic parameters. In this group of patients no cular function or reduction of compliance in case of increased PVR or need for CISC was noted even the bladder injection repetition. with a dose of 300 UI of BTX. In order to avoid In the last year several investigators sug- acute urinary retention or PVR, all patients had 50- gested that BTX might affect urothelium/ 75 UI of the BTX concurrently injected into the ex- suburothelium sensory innervations. BTX-A has ternal sphincter without increasing stress inconti- been found to reduce pathologically elevated levels nence rate. of neurotransmitters including ATP, to decrease the Several studies supported the BTX as prom- number of suburothelial afferent neurons express- ising therapy in urological disease conditions as pre- ing purinergic receptors and to reduce urgency viously described, however additional investiga- (57,58). The exact mechanism of action on the af- tions, including controlled clinical trials, are needed. ferent pathway remains unknown. Further studies of the mechanism of action of botu- Following the remarkable efficacy seen in linum toxin and its pharmacotherapeutics are also studies with NDO, a number of researchers have in- needed and international standardization of measures vestigated BTX use in patients suffering from of biological activity of botulinum toxin is requested. antimuscarinic refractory IDO. Chancellor was the We strongly suggest that for most of urological in- first to investigate the effect of BOT in a group of dications, botulinum toxin should be used by com- patients with overactive bladder refractory to other mitted interdisciplinary teams of physicians and re- conservative treatments (59). Rapp investigated the lated health care professionals with appropriate in- effects of injection of botulinum toxin in thirty-five strumentation to assess the clinical beneficial as well patients (29 women and 6 men) with frequency, ur- as objective and sub clinical side effects. The long- gency, and/or urge incontinence (60). The patients term effects of chronic treatment with botulinum received 300 UI of BTX-A injected transurethrally toxin remain unknown. Prolonged follow-up is nec- at 30 sites within the bladder. Overall, 21 (60%) of essary in patients on maintenance therapy and an 35 patients reported slight to complete improvement international independent database should be estab- of voiding symptoms after 3 weeks. Among the ini- lished. tial responders followed up for 6 months an improvement of quality of life was reported in most patients with fewer side effects. Due to the increased under- CONCLUSION standing of the role of the urothelium in OAB, Kuo assessed sub-urothelial injections of BTX (61). It Generally new therapies are supposed to be was found that although this method of administra- better than the treatment they replace and not to in- tion was more effective than detrusor injections, duce any side effects. Studies of an alternative treat- there was impaired bladder sensation and voiding ment to antimuscarinics for overactive bladder (OAB)

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61. Kuo HC: Clinical effects of suburothelial injection of 62. Schulte-Baukloh H, Weiss C, Stolze T, Sturzebecher botulinum A toxin on patients with nonneurogenic de- B, Knispel HH: Botulinum-A toxin for treatment of trusor overactivity refractory to anticholinergics. Urol- overactive bladder without detrusor overactivity: ogy. 2005; 66: 94-8. urodynamic outcome and patient satisfaction. Urology. 2005; 66: 82-7.

Accepted: June 16, 2006

Correspondence address: Dr. Massimo Lazzeri Department of Urology Casa di Cura Santa Chiara Firenze, Piazza Indipendenza 11, 50129, Firenze, Italy Fax: + 39 05 548-0676 E-mail: [email protected]

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