Novel Treatments for Men with Lower Urinary Tract

NEWS AND PERSPECTIVES

Novel Treatments for Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostate Hyperplasia Shiu-Dong Chung,1,2 Hong-Jeng Yu2*

Lower urinary tract symptoms (LUTS) are prevalent among men. LUTS are divided into three categories: storage, voiding, and postmicturition. According to the definition by the International Continence Society, storage LUTS are composed of the symptoms of overactive bladder (OAB) and urgency with or without urgency incontinence, usually with frequency and nocturia.1 Storage LUTS are often associated with bladder outlet obstruction due to benign prostate hyperplasia (BPH) in men. The pathophysiology of male LUTS that is suggestive of BPH is multifactorial. Thus, the therapeutic target shifts from the prostate and use of α-antagonists, 5-α-reductase inhibitors and surgical intervention to the urinary bladder.2 Recent investigations have shown that multiple pathways are involved in bladder dysfunction. Therefore, several novel strategies to treat BPH and LUTS are briefly discussed.

receptors. During bladder filling, the drugs suppress involuntary detrusor contractions caused by basal release of neuronal and urothelial acetylcholine. During the voiding phase, massive parasympathetic outflow and acetylcholine release might overcome the effects of antimuscarinic medication. A prospective randomized study demonstrated that men with symptoms suggestive of both BPH and OAB showed significant improvements in LUTS with tolterodine extended release and tamsulosin, an α-adrenergic antagonist, compared with placebo, tolterodine extended release alone, or tamsulosin alone.1 There is increasing evidence to show that men with OAB and obstructive or non-obstructive BPH can benefit from tolterodine with or without α-blockers and are at low risk for acute urinary retention, increased postvoid residual, or acute urinary tract infection.4,5

b3-adrenoreceptor Agonists Antimuscarinic Medication Real-time reverse transcription–polymerase chain reaction analysis revealed the predominant expression of β3-adrenoreceptor (AR) mRNA in the human detrusor muscle, which was 97% of total β-ARs.6 Functional studies have demonstrated that AR agonist-evoked relaxation is mediated primarily by β3-ARs in human bladder tissue.7,8

Recent studies have demonstrated both the effectiveness and safety of antimuscarinic drug and α-antagonist combinations, improving both urodynamic and patient-reported outcomes in men with LUTS and BPH.1–3 Anticholinergic drugs are competitive antagonists of bladder muscarinic

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Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Ban Ciao, Taipei, and 2Department of Urology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan. *Correspondence to: Dr Hong-Jeng Yu, Department of Urology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]

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S.D. Chung, H.J. Yu

In vivo studies indicate that β3-AR agonists increase bladder capacity with no change in micturition pressure and residual volume, indicating that β3-AR agonists are useful in storage symptoms secondary to obstructed bladder.9

of patients with urinary urgency, particularly if refractory to the anticholinergic agents, and may also improve BPH-associated storage symptoms.11

Botulinum Toxins Purinoceptor Antagonists Adenosine triphosphate (ATP) can be released by distension of the bladder and activation of the micturition reflex. The ATP receptor, P2X3, is expressed on small diameter primary sensory neurons and urothelium, and analysis of bladder biopsies from patients with detrusor overactivity revealed increased P2X3 receptors in these patients. Given the emergent roles of ATP, modulation of P2X receptor activity has been thought to be a potential target of therapeutic intervention in LUTS. Activation of recombinant and native P2X3 and P2X2/3 receptors was inhibited by submicromolar concentrations of A-317491, and efficacy was demonstrated in several models of chronic inflammatory and neuropathic pain. Lu et al recently demonstrated that A-317491 inhibits non-micturition bladder contractions without affecting voiding contractility in a rat spinal cord injury model.10 Improving the pharmacokinetics and bioavailability of both of these potential drugs will increase the treatment potential.

Vanilloid Receptors The role of vanilloid receptors such as transient receptor potential vanilloid (TRPV-1) in the pathophysiology of neurogenic or idiopathic detrusor overactivity has been recognized. C-fiber input plays an important role in the generation of the urgency sensation. Resiniferatoxin (RTX) is the sole compound with a desensitizing effect suitable for human use. Furthermore, bladder instillation of vanilloid agents, such as capsaicin and RTX, resulted in increased bladder capacity and decreased urge incontinence. Finally, bladder desensitization by RTX was useful in the treatment 350

Botulinum neurotoxin type-A (BoNT-A) induces prostate cell apoptosis and decreases cell proliferation in a dose-dependent manner. Some animal studies have shown that relaxation of the prostate is due to α1-adrenergic receptor downregulation of stromal smooth muscle cells and impaired release of norepinephrine from adrenergic nerve endings.12,13 BoNT-A has been proven to be effective in reducing detrusor overactivity, and the efficacy of BoNT-A on LUTS due to BPH has also been demonstrated. Kuo evaluated the effectiveness of BoNT-A injection into the prostates of BPH patients and reported that all patients experienced improvements in spontaneous voiding.14 Further information, including dosing, effect duration, effect on prostate size, prostate-specific antigen, and repeated injections, are required in future evaluations.

Endothelin Antagonists Endothelins have a direct contractile effect on prostatic smooth muscle cells, may enhance α1receptor-mediated smooth muscle contraction, and stimulate cell proliferation. Endothelin-1 (ET-1) is an endogenous vasoactive peptide that binds two receptor subtypes, the endothelin-A (ETA) and endothelin-B (ETB) receptors. ET-1 can directly activate C-fiber afferent nerves in the bladder, and suppression of ETA receptors might be effective for the treatment of detrusor overactivity by reducing activation of C-fiber afferent pathways. Bladder hypertrophy is common in various pathologies of the bladder or its outlets, such as BPH or neuropathic bladder, including spinal cord injury (SCI).15 In vitro studies with smooth muscle cells obtained from obstructed rabbit bladders have shown that endothelin antagonists inhibit smooth J Formos Med Assoc | 2009 • Vol 108 • No 5

Novel treatments for men with LUTS suggestive of BPH

muscle cell proliferation.16 Taken together, endothelin antagonists are effective against OAB. 3.

Phosphodiesterase-5 Inhibitors 4.

The association between LUTS and erectile dysfunction (ED) has been increasingly recognized and investigated. ED, ejaculatory disorders, and pain during intercourse are correlated with the severity of LUTS, and several studies have reported LUTS to be an independent risk factor for the development of ED.17,18 Several pathophysiologies common to LUTS and ED, such as age, atherosclerosis-induced vascular insufficiency in the bladder and corpora, and autonomic nervous system hyperactivity, have been reported and are potentially mediated by nitric oxide pathways. In addition, there are significant amounts of phosphodiesterase types 4 and 5 in the transition zone of the prostate. Given the potential common etiology of LUTS and ED, phosphodiesterase-5 inhibitors and α-blockers are advantageous to both diseases.

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Conclusion 10.

The available reports regarding these novel medical therapies for LUTS in men demonstrated them to be effective. In addition, other pharmaceutical therapies, including angiotensin receptor antagonists, vitamin D3 receptor analogs and rho-kinase inhibitors, that are associated with blocking prostate growth and relieving LUTS are under investigation.

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