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PERSPECTIVES IN PHARMACOLOGY

Emerging Pharmacologic Approaches for the Treatment of Lower Urinary Tract Disorders

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Received for publication August 22, 2003
Accepted December 16, 2003.

	Abstract

Top Abstract Incontinence Benign Prostatic Hyperplasia Male Erectile Dysfunction Future Prospects References

 
Lower urinary tract disorders include disorders affecting continence (stress urinary incontinence, urge urinary incontinence, and benign prostatic hyperplasia) and male erectile dysfunction. Although none of these conditions are fatal, they affect overall quality of life. Throughout modern medicine the treatment of these conditions was limited to psychological counseling or surgical intervention. In recent years, research defining the physiological mechanisms of continence and male sexual function has aided in the pharmacologic design of approaches to these conditions. These agents can act both centrally or on the peripheral genitourinary smooth muscle to alleviate disease symptoms. Incontinence is primarily treated with agents that act directly on the bladder smooth muscle such as muscarinic antagonists. However, afferent blockade to attenuate the spinalbulbospinal reflex pathway including mixed norepinephrine/serotonin reuptake inhibitors may provide a key breakthrough. Erectile dysfunction treatment has been revolutionized via the discovery of the nitric oxide pathway and phosphodiesterase 5 inhibitors. New peripheral targets as well as centrally acting agents represent potential emerging therapies. In this review, the pharmacologic basis of treatment of these disorders is discussed with special emphasis on emerging new therapeutics.

	Incontinence

Top Abstract Incontinence Benign Prostatic Hyperplasia Male Erectile Dysfunction Future Prospects References

 
The biochemical and pharmacologic basis of continence as well as a discussion of physiology and pathophysiology have been reviewed in detail and will only be briefly discussed here (de Groat and Yoshimura, 2001; Yoshimura and Chancellor, 2002). The urinary bladder functions as a reservoir for the storage and release of urine via the urethra (6–8 times/24 h). The storage and periodic elimination of urine also depends on the coordinated activity of the bladder and urethra (outlet). During storage, the outlet is closed, and the bladder smooth muscle is quiescent such that intravesicular pressure is low and constant over various bladder volumes. During voiding, the muscles of the outlet relax and the bladder smooth muscle contracts. The expulsion phase consists of an initial relaxation of the urethral sphincter followed in a few seconds by a contraction of the bladder, an increase in bladder pressure, and flow of urine.

Bladder function is coordinated by three sets of nerves arising from the sacral (excitatory cholinergic and purinergic nerves to bladder and inhibitory nitergic nerves to the urethra) and thoracolumbar vertebrae in the spinal cord (sympathetic nerves to urethra and bladder neck). Three sets of afferent neurons arise in the bladder and go to the spinal cord: small myelinated A fibers, unmyelinated C fibers and afferents from the urothelium. These urothelial afferents can sense changes in composition of urine as well as ATP, nitric oxide (NO), or prostaglandins. CNS control of voiding is via a spinobulbospinal reflex arc and the rostral brain stem (pontine micturition center) (de Groat and Yoshimura, 2001). Higher centers in the cerebral cortex and diencephalons underlie the voluntary mode of voiding.

Involuntary loss of urine (urinary incontinence) occurs when pressure inside the bladder (intravesical pressure) exceeds the retentive pressure of the internal urethral sphincter and external urethral sphincter (intraurethral pressure). A glossary of terms used in LUTD is provided in Table 1. From a clinical perspective, incontinence denotes a symptom, a sign, and a condition (Abrams et al., 2003). The symptom indicates the patient's (subjective) statement of involuntary urine loss; the sign is the objective demonstration of urine loss (by the physician); and the condition is the underlying pathophysiologic process as demonstrated by clinical or urodynamic techniques. Due to the complex inter-relationships between CNS input, inhibitory regulation, and peripheral myogenic components, incontinence can have both myogenic and/or neurogenic etiologies. The prevalence of incontinence (10–13 million in the United States; 17–20 million outside the United States) is comparable to that of cancer, diabetes, and BPH.

Urge Urinary Incontinence/Overactive Bladder
Urge urinary incontinence (UUI) is the complaint of involuntary leakage accompanied by or immediately preceded by a strong desire to void (urgency) (Abrams et al., 2003). In contrast, overactive bladder syndrome is a condition with symptoms of urgency with or without incontinence and usually with increased frequency and nocturia. Approximately 25% of all incontinence patients suffer from overactive bladder syndrome. This syndrome is associated with the urodynamic finding of involuntary bladder contractions, referred to as bladder instability. UUI differs in symptoms and etiology from stress urinary incontinence (SUI). Bladder instability can have a myogenic etiology in which smooth muscle function is impaired as a result of a partial urethral outlet obstruction (as in BPH), or it can be idiopathic. In a recent study, it was found that 50 to 80% of men with BPH suffer the irritative symptoms of bladder instability (Elliott and Boone, 2000). Instability may also be of neurogenic origin (e.g., Alzheimer's disease, Parkinson's disease, or stroke), which is generally referred to as bladder hyperreflexia.

Myogenic Etiology. In some cases, the symptoms of overactive bladder syndrome may be due to disorders of smooth muscle tone. Bladder tissues from these patients show distinct features at the smooth muscle level predisposing them to unstable contractions. The loss of normal excitatory neural input results in increased signaling between smooth muscle cells, leading to a state of overactivity. Acute sensitivity to agonists increases in gap junctions and enhanced electrical coupling between smooth muscle cells enables widespread depolarization signals sufficient to cause spontaneous muscle activity resulting in increased intravesical (bladder) pressure (Yoshimura and Chancellor, 2002).

Neurogenic Etiology. The symptoms of overactive bladder syndrome may also be triggered by neurologic defects or trauma (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, spinal cord injury, and stroke). In this case, a loss of inhibition of the sacral reflex through the pelvic nerve alters reflex regulation of bladder and urethral function leading to bladder hyperreflexia.

As noted above, another mechanism involves afferent signaling activity where the major component of the afferent input from the bladder to the CNS is mediated by C-fibers originating in the bladder urothelium (Yoshimura and Chancellor, 2002). These afferents control voiding reflexes in infancy, and a body of evidence suggests that the re-emergence of C-fiber reflexes may underlie some facets of bladder overactivity.

Pharmacological Approaches to the Treatment of UUI
Muscarinic Antagonists. Both M₂ and M₃ muscarinic acetylcholine receptors (mAChR) play a role in voiding mechanisms (Chapple et al., 2002). Although M₂ mAChR are more abundant than M₃ mAChR in the lower bladder dome and in the base, M₃ gene knockout mice showed urinary retention whereas M₂ gene knockout mice did not (Matsui et al., 2000; Stengel et al., 2000). In organ bath experiments, bladder strips from M₂ gene knockout mice had impaired contractility to carbachol compared with wild type, indicating that the M₂ mAChR does play some role in bladder contractility and the voiding mechanism (Stengel et al., 2000). This may especially apply during pathophysiologic changes such as outflow obstruction where M₂ receptors play the key role in bladder contraction in a rat model (Braverman and Ruggieri, 2003).

Muscarinic antagonists take advantage of the role of M₂ and M₃ mAChR receptors in bladder contraction and inhibit these receptors decreasing the response to acetylcholine. These agents reduce pressure during bladder filling and treat unstable bladder contractions. Although nonselective agents such as atropine are effective in treating overactive bladder, they have the unwanted side effect of xerostomia (dry mouth) presumably from inhibition of M₃ mAChR in the salivary glands.

Oxybutynin is a potent, competitive muscarinic antagonist that has been a mainstay of therapy for more than 20 years (Table 2) (Rovner and Wein, 2000; Yoshimura and Chancellor, 2002). Studies using binding assays to characterize oxybutynin report 6-fold selectivity of M₃ over M₂ and 4-fold M₃ over M₅ but little selectivity between M₁, M₃, and M₄ (Eglen et al., 2001). The N-desethyl metabolite of oxybutynin in humans may be responsible for inducing dry mouth. Clinical trial data measuring the decrease in the number of voids and extent of leakage show statistically significant but minimal improvement between placebo and oxybutynin treatment (comparing extended release to three times daily dosing; both treatments had similar efficacy reducing number of visits 24% compared to 9% in the placebo control group; Nilsson et al., 1997).

Tolterodine is also a competitive, muscarinic antagonist that has similar potency on bladder muscarinic receptors as oxybutynin but 8-fold less potency for parotid gland receptors (greater uroselectivity). There is little selectivity for the five muscarinic receptors by binding assays except 2-fold M₃ over M₄ (Eglen et al., 2001). In clinical trials and in head-to-head comparisons of immediate release oxybutynin, tolterodine shows similar efficacy but tolterodine is better tolerated (Nilvebrant, 2001).

Darifenacin is an M₃-selective antagonist with 60-fold more potency for M₃ over M₂ mAChR and 9-fold selectivity for bladder versus salivary gland receptors (Chapple et al., 2002; Yoshimura and Chancellor, 2002). The Food and Drug Administration (FDA) approved this agent for treatment of overactive bladder in October of 2003.

Purinergic Antagonists. Pathological conditions such as denervation or inflammation can cause ATP release that in turn promotes nonadrenergic, noncholinergic bladder contractions. Intravesical ATP, as well as ,-methylene ATP, stimulate the mictutrition reflex in freely moving, awake rats, a process that could be blocked with neurokinin-2 antagonist SR48968, potassium channel opener ZD6169 or ganglionic blocker hexamethonium (Pandita and Andersson, 2002). NO, involved in this process as L-NAME, a nonspecific inhibitor of NO synthase, blocked this process. ATP can act on two families of receptors: G-protein-coupled receptor P2Y family and ion channel P2X family (Burnstock, 2002). Immunolocalization experiments as well as in situ hybridization experiments in rats and humans have identified P2X₁ and P2X₄ receptors in the detrusor and P2X₃ in small diameter afferent neurons in the dorsal root ganglia (Yoshimura and Chancellor, 2002). P2X₃ knockout mice suffer from bladder hypoactivity, decreased afferent activity, and a loss of augmented bladder distension to intravesical P2X agonists (Vlaskovska et al., 2001), suggesting a role for ATP released from the urothelium and P2X₃ in bladder function. It has been hypothesized that by attenuating afferent mechanisms, incontinence could be successfully treated (Yoshimura and Chancellor, 2002). The recent discovery of small molecule non-nucleotide P2X₃ antagonists (Jarvis et al., 2002) could offer proof of principle of this class of therapeutics.

Vanilloid and Tachykinin Receptors. Vanilloids such as capsaicin and resiniferatoxin can activate nociceptive sensory nerve fibers via the VR1 receptor. The observation that intravesicular capsaicin as well as resiniferatoxin activate and desensitize VR1 receptors and decrease bladder hyperactivity suggests that a VR1 agonist might have a therapeutic role (Yoshimura and Chancellor, 2002). This therapy may be particularly valuable in denervated, hyperactive bladders where the VR1 and purinergic pathways exert a key role in bladder hyperactivity via afferent pathways in the spinalbulbospinal reflex pathway (de Groat and Yoshimura, 2001; Yoshimura and Chancellor, 2002). Homozygous mice with a VR1 gene knockout have a higher frequency of low amplitude and nonvoiding bladder contractions and under anesthesia, show reductions in the afferent bladder signaling during filling (Birder et al., 2002). Small molecule agonists of the VR1 receptor are eagerly awaited to better understand the therapeutic potential of blockade of this receptor. Immunocytochemical studies of bladder afferent neurons reveal colocalization of neuropeptides including calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), enkephalins, neurokinin A, and substance P on capsaicin-sensitive C-fiber bladder afferents. Bladder hyperactivity induced by capsaicin was reduced by intrathecal administration of neurokinin-1 antagonists. As mentioned above, neurokinin-2 antagonist SR48968 blocked the effects of intravesicular ATP on voiding in rats, suggesting NK-2 inhibition of P2X receptors (Pandita and Andersson, 2002). A highly selective neurokinin-1 antagonist TAK637 has been reported to be effective in suppressing guinea pig bladder activity and is in Phase II clinical trials in humans for UUI (Furness, 2001).

Potassium Channel Openers. Hyperpolarzation of bladder smooth muscle cell membrane potential is regulated in part by potassium concentration. The bladder expresses K-ATP potassium channels that have been shown to play a role in bladder contraction and hyperactivity due to their ability to modulate the membrane potential of bladder smooth muscle (Yoshimura and Chancellor, 2002). Openers of K-ATP channels can suppress myogenic bladder contractions by relaxing bladder smooth muscle cells via membrane hyperpolarization. A key challenge in the development of this class of therapeutics is the ability to separate lower urinary tract effects from cardiovascular effects where these channels are also expressed. In a limited clinical trial for overactive bladder, for example, cromakalin reduced patient symptoms 35% but had unacceptable hypotension at the effective doses (Nurse et al., 1991). A number of agents with enhanced uroselectivity versus cromakalin have been described in recent years including ZD6169, WAY133537, and A-278637 (Brune et al., 2002; Fabiyi et al., 2003). However, whether or not this favorable preclinical profile can be translated into a desirable clinical profile in humans with acceptable cardiovascular liabilities remains to be determined.

Stress Urinary Incontinence
SUI is the complaint of involuntary leakage of urine on effort or exertion or on sneezing or coughing coincident with an increase in intra-abdominal pressure in the absence of a bladder contraction or an overdistended bladder (Abrams et al., 2003). This is the most common form of incontinence, affecting approximately 35% of all UI patients.

The most common causes of SUI in women are urethral hypermobility and intrinsic urethral sphincter deficiency. Urethral hypermobility is characterized by a weakness of the pelvic floor support. This may have congenital origins or may be acquired after surgery, trauma, or a sacral cord lesion. In females, intrinsic urethral sphincter deficiency is commonly associated with multiple incontinence surgical procedures, as well as hypoestrogenism, aging, or both. In this condition, the urethral smooth muscle and sphincter are unable to generate enough resistance to retain urine in the bladder.

Pharmacological Approaches to the Treatment of SUI
Alpha Adrenoceptor Agonists. Noradrenergic input to smooth muscle of the urethra is abundant in marked contrast to the bladder (de Groat and Yoshimura, 2001). Studies in rats, cats, and dogs indicate that sympathetic input to the urethra is tonically active during bladder filling. Substantial preclinical physiological, pharmacological, and molecular biological evidence suggests that _1A adrenoceptors are responsible for mediating the effects of norepinephrine on urethral tone and intraurethral pressure (Testa et al., 1993). Clinical studies with the nonselective -adrenoceptor agonists, phenylpropanolamine and midodrine have demonstrated limited clinical efficacy (Sullivan and Abrams, 1999). The limited efficacy of these nonselective agents has been attributed to effects on blood pressure and heart rate that occur at doses comparable to those eliciting an effect on urethral function.

A number of highly selective agonists for the _1A subtype relative to the _1B subtype have been generated in an effort to generate the necessary selectivity for urethra versus vasculature. Unfortunately, only modest improvements in urethral selectivity have been noted with these agents in preclinical models (Buckner et al., 2002). Although compounds such as ABT-866 are highly selective _1A agonists, only very modest uroselective effects are observed (Buckner et al., 2002). Increases in blood pressure are observed at doses 3- to 10-fold higher than those where effects on urethral pressure are observed. Even small increases (e.g., 2–5 mm Hg) in blood pressure are unlikely to be acceptable clinically in humans.

Serotonin, Norepinephrine-Reuptake Inhibitors. Serotonin (5-hydroxytryptamine, 5-HT) plays an important central role in the inhibition of the micturition reflex, probably through 5-HT_1A receptors in the raphe. Both 5-HT and the serotonergic agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased bladder capacity when injected intracerebroventricularly (i.c.v.) to conscious rats stimulated micturition, a process that could be blocked by i.c.v. administration of the selective 5-HT_1A antagonists WAY100635 or NAD-299 (Pehrson et al., 2002). Neither antagonist had any effect on bladder muscle strips in organ baths either electrically stimulated or precontracted with carbachol. It has further been demonstrated in the urethaneanesthetized rat that WAY100635 injected intracerebroventricularly blocked micturition reflex contractions (Yoshiyama et al., 2003). Mesulergine (5-HT_2C antagonist) abolished the effects of WAY100635, possibly via spinal receptors. These results suggest that the frequency of micturition reflexes via the afferent pathway to the pons micturition center are regulated in part by 5-HT_1A receptors whereas the regulation of bladder contraction is regulated via output from the pons and parasympathetic pathways.

The importance of serotonin in the CNS regulation of both parasympathetic and somatic neural projections to the bladder has prompted the investigation of the serotonin and norepinephrine-specific re-uptake inhibitor duloxetine on bladder function in felines (Khaled and Elhilali, 2003). The investigators concluded that duloxetine suppressed bladder activity by increasing bladder capacity through serotonergic mechanisms while enhancing bladder sphincter contraction via 5-HT₂ receptors (consistent with the study above) and -adrenergic mechanisms. This agent may work through a dual mechanism of norepinephrine action on the urethra as well serotonergic mechanism (Khaled and Elhilali, 2003; Viktrup and Bump, 2003). A 12-week, double blind, placebo-controlled Phase III clinical trial of duloxetine in 683 women 22 to 84 years of age with SUI showed a significant decrease of incontinence episode frequency with duloxetine (51%) compared with the placebo control (31%) (Dmochowski et al., 2003). Discontinuation rate for duloxetine was 24% with the most common side effect being nausea. The FDA issued an approvable letter for duloxetine for the treatment of stress incontinence in September of 2003. Approval is contingent on successful completion of additional acute preclinical and clinical pharmacology studies and is anticipated in late 2004 or the first half of 2005.

	Benign Prostatic Hyperplasia

Top Abstract Incontinence Benign Prostatic Hyperplasia Male Erectile Dysfunction Future Prospects References

 
BPH is a term reserved for the typical histological pattern that defines the disease (Abrams et al., 2003). As hyperplasia occurs, the prostate can enlarge without urethral obstruction (no LUTS). Benign prostatic obstruction is a form of bladder outlet obstruction and may be diagnosed as BPH with LUTS when the cause is due to histologic BPH (Abrams et al., 2003; Thorpe and Neal, 2003). By age 40, BPH is present in 8% of men increasing to 60% by age 70 and 90% over 80 years of age. BPH with LUTS include complaints of nocturia (nighttime voiding) as well as difficulty voiding and increases in urgency and frequency. One-third of men over 50 years old will develop some form of lower urinary tract symptoms with 25% of these requiring surgery (for example, transurethral resection of the prostate).

Current pharmacologic treatment of BPH utilizes ₁-adrenoceptor antagonists and 5--reductase inhibitors that block testosterone production (Thorpe and Neal, 2003). The mode of action of ₁-adrenoceptor antagonists has been thought to be prostate smooth muscle and stromal relaxation and relaxation of the urethra with a subsequent increase in urinary flow (Andersson, 2002). One hypothesis is that these agents increase apoptosis in both prostate glandular epithelial and stromal smooth muscle cells after about 6 months of treatment, and the resulting decrease in prostate size increases urinary flow rate upon voiding. However, this has only been demonstrated in vitro and has yet to be confirmed in a clinical setting. Tamsulosin, doxazosin, and terazosin nonselectively antagonize ₁-adrenoceptors (O'Leary, 2001; Andersson, 2002). As in the case with muscarinic antagonists in the treatment of UUI, ₁-adrenoceptors fail to fully relieve the symptoms associated with BPH. An example of treatment efficacy is seen in the tamsulosin trials where after 53 weeks of treatment the percentage of respondents with 25% improvement in LUTS was 51% with placebo, 70 and 74% with 0.4 and 0.8 mg/day tamsulosin, respectively. The same study showed that the percentage of respondents with a 30% improvement in maximum urinary flow rate were 21% for placebo and 31 and 36% with 0.4 and 0.8 mg/day tamsulosin, respectively (O'Leary, 2001). The uroselective ₁-adrenoceptor antagonist alfuzosin is in late stage clinical trials and may provide another agent in this armamentarium (Hofner and Jonas, 2002).

The prostate contains both type I and II 5--reductase activities, which convert testosterone to the more active dihydrotestosterone. Finasteride an azosteroid is a type II 5--reductase inhibitor that results in atrophy of the prostatic glandular epithelium when taken due to a decreased synthesis of dihydrotestosterone. Although onset is slow, treatment results in a long-lasting 20 to 30% reduction in prostate volume and a decrease in LUTS. Side effects include ejaculatory dysfunction (up to 8%), loss of libido (up to 10%), and erectile dysfunction (up to 16%). Dutasteride (a type I and II 5--reductase inhibitor) reduces risk of urinary retention 48 to 57% compared with placebo (Thorpe and Neal, 2003). Most recently, a double blind multicenter trial in over 1000 patients, comparing placebo, doxazosin, finasteride, and combination therapy, found that combination therapy was no more effective over 1 year in increasing urinary flow rate and reducing LUTS scores than either treatment alone (Kirby et al., 2003).

	Male Erectile Dysfunction

Top Abstract Incontinence Benign Prostatic Hyperplasia Male Erectile Dysfunction Future Prospects References

 
MED is defined as the persistent and consistent inability to achieve penile erection during sexual stimulation (Moreland et al., 2001b). This condition occurs in varying degrees of impairment increasing in incidence with aging and associated with cardiovascular disease, hypertension, diabetes, neurological conditions, and depression (Kubin et al., 2002). The worldwide prevalence of MED has been estimated at over 152 million men, and the projections for 2025 estimate a prevalence of approximately 322 million with MED. Reports of quality of life data suggest that the importance of MED in contributing to other chronic health conditions such as depression has been largely underestimated. Over the past 30 years, the biochemical and pharmacologic basis for penile erection has revealed that this event involves a complex integration of CNS input, hemodynamics, and vascular smooth muscle relaxation within the corpora cavernosa of the penis. These processes as well as discussion of pathophysiology, epidemiology, and physiology have been reviewed in detail and will only be briefly discussed here (Andersson, 2001; Moreland et al., 2001b).

Penile erection is a spinal reflex under CNS (supraspinal) inhibitory control. Visual, tactile, olfactory and imaginative stimuli from the higher cortical areas of the brain are integrated in the medial preoptical area of the hypothalamus with processes that involve dopaminergic and oxytocinergic neurons. The nonselective D₂-like agonist apomorphine increased blood flow to the anterior cingulum and the right prefrontal cortex during sexual stimulation as measured by positron emission tomography (Hagemann et al., 2003). Mapping of these neurons and understanding which of the D₂-like receptors mediate this process has yet to be reported. These neurons send an impulse that results in the release of NO from nitrergic neurons in the corpus cavernosum penis allowing vasodilation due to activation of smooth muscle soluble guanylate cyclase by NO. NO is also released as a result of action of shear stress and acetylcholine on the corpus cavernosum endothelium. Vasodilation ensues and veno-occlusion occurs upon filling. Pharmacologic targets for the treatment of MED can be divided into central and peripheral. Central nervous system targets are the least explored and take advantage of the known pathways including dopamine and melanocortin. Peripheral targets primarily rely on enhancing smooth muscle vasodilation or blocking the adrenergic or endothelin-mediated vasoconstriction associated with penile flaccidity. As vasodilators, these agents have the challenge of penile-specific effects with limited cardiovascular liabilities.

Four agents are currently approved by the FDA for treatment of erectile dysfunction [prostaglandin E₁ (PGE₁), and three phosphodiesterase (PDE) 5 inhibitors] whereas apomorphine is approved for use in Europe and Japan (Table 2). The discovery of NO as one of the major substances in vasodilation of the corpus cavernosum and the onset of penile erection led to the discovery of PDE5 inhibitors as therapeutic agents for the treatment of MED (Corbin and Francis, 2002). PDE5 inhibitors block the hydrolysis of cGMP that is synthesized by soluble guanylate cyclase in response to NO release. Thus, PDE5 inhibitors enhance the existing NO effects by prolonging cGMP levels in the smooth muscle. Sildenafil was the first oral therapeutic for MED and was FDA approved in 1998. Sildenafil is a potent inhibitor of PDE5, the predominant isoform in the corpus cavernosum smooth muscle (IC₅₀ = 5.3 nM). In dose escalation studies of sildenafil, 69% of men achieved erections sufficient for intercourse versus 22% in the placebo control group. The inhibition of PDE1 and PDE6 are also of interest because inhibition of these isoforms that are expressed in vascular and retinal cells may be responsible for the side effects of sildenafil (hemodynamic effects and blue vision). Sildenafil exhibits a 40-fold PDE5/PDE1 ratio and a 5-fold PDE5/PDE6 ratio; however, the plasma levels reached by the 100-mg pill are 450 ng/ml (950 nM) so at these plasma levels PDE5, PDE6, and PDE1 are all inhibited. As PDE5 inhibitors potentiate the effects of NO, coadministration with nitrates (angina) and patients with moderate to severe cardiovascular disease are contraindicated (Moreland et al., 2001b).

Tadalafil is a potent inhibitor of PDE5 with an IC₅₀ = 3.6 nM and exhibits better PDE5/PDE1 and PDE5/PDE6 ratios than sildenafil (Corbin and Francis, 2002). In human cavernosal cells, tadalafil potentiates the accumulation of cGMP induced by sodium nitroprusside, and it enhances the relaxation induced by electrical stimulation in human cavernosal strips at 30 nM. Tadalafil relaxes rabbit cavernosal cells precontracted with phenylephrine with IC₅₀ = 138 nM (similar to the potency of sildenafil, IC₅₀ = 135 nM).

Two types of clinical trials have been conducted with tadalafil: on demand (5, 10, and 25 mg) and a 3-week treatment to provide 24 h coverage (20 mg dose) to capitalize on the long half-life of tadalafil (17.5 h) (Brock et al., 2002; Porst et al., 2003). In a recent trial to demonstrate efficacy up to 36 h after dosing, 59% of men taking 20 mg of tadalafil had successful intercourse attempts versus 28% in the placebo control group (Porst et al., 2003). In an analysis of five of the clinical trials with tadalafil, 75% of men taking the 20 mg dose had successful intercourse attempts versus 32% in the placebo control group (Brock et al., 2002). The FDA approved tadalafil for treatment of MED in November of 2003.

Vardenafil is a potent PDE5 inhibitor (IC₅₀ = 0.4 nM) that exhibits a similar PDE5/PDE1 or PDE5/PDE6 ratio to sildenafil. Vardenafil can relax rabbit cavernosal strips precontracted with phenylephrine with IC₅₀ = 164 nM. It has a half-life of 3.9 h in humans. In a 26-week Phase III trial, 79.7% of men taking 20 mg of vardenafil were able to have erections sufficient for intercourse versus 50% in the placebo control group (Hellstrom et al., 2003). The FDA approved vardenafil for treatment of MED in August of 2003.

Soluble guanylate cyclase (sGC) activators synergistically enhance the effects of NO by stimulating cGMP synthesis without altering the breakdown of cGMP (Brioni et al., 2002). Both A-350619 and BAY41–2272 allosterically activate sGC in vitro while inducing penile erection in animal models in vivo (Bischoff et al., 2003; Miller et al., 2003). However, all of these agents have yet to advance beyond the preclinical research stage.

The blockade of endogenous vasoconstrictor-induced corpus cavernosum smooth muscle tone has been proposed as a means of inducing penile erection. However, the nonselective -adrenoceptor antagonist phentolamine has been recently withdrawn from clinical development after a modest demonstration of efficacy in men with mild to moderate MED (Padma-Nathan et al., 2002). Similarly, endothelin antagonists were thought to be a treatment of MED given the presence and potent contractile activity of endothelins (ET) in vitro in this tissue (Andersson, 2001). However, efficacy in vitro studies with ET_A-selective receptor, selective antagonist BMS-193884 on rabbit and human corpus cavernosa, fail to confirm these hypotheses in a limited human clinical trial where no improvement of erectile function could be demonstrated (Kim et al., 2002). The recent discovery that the Rho kinase inhibitor Y-27632 potentiates penile erection has generated a renewed interest in understanding the contractile pathways involved in penile flaccidity and potentiation of erection (Chitaley et al., 2003). The ubiquitousness of the pathway raises some concerns regarding cardiovascular side effects (e.g., hypotension). Rho kinase inhibitors have yet to advance beyond the preclinical research stage.

Whereas NO-cGMP actions are important in penile erection, cAMP-mediated pathways via vasoactive intestinal peptide, CGRP or endogenous prostaglandin E₂ (PGE₂) may also play a role in penile erection (Andersson, 2001; Moreland et al., 2001a,b). PGE is synthesized by the corpus cavernosum endothelial and smooth muscle cells and binds to specific PGE (EP₂ and EP₄) receptors on the smooth muscle in turn increasing intracellular cAMP synthesis and potentiating smooth muscle relaxation (Moreland et al., 2001a). PGE₁ continues to be an efficacious agent despite injection and intraurethral delivery.

One of the pharmacologic goals in the treatment of male erectile dysfunction has been to delineate the CNS pathways and develop an orally dosed, CNS-acting agent that can treat MED. Both dopaminergic agonists and melanotonin agonists have been explored. Dopamine plays a key role as a CNS neurotransmitter in sexual function and penile erection (Moreland et al., 2001b). Injections into the medial preoptic area of the hypothalamus of rats of apomorphine or quinelorane, both nonselective D₂ agonists, induced penile erections in rats. Apomorphine is the first CNS-acting agent approved for treatment of MED (in Europe in 2001). In a Phase III trial to compare dosing between 3 and 4 mg of sublingual apomorphine with placebo, it was found that 46.9% of men taking 3 mg and 49.4% of men taking 4 mg had erections sufficient for intercourse versus 34% in the placebo control (Dula et al., 2001). Since apomorphine is an agonist at all three D₂-like receptors, it is possible that a selective dopaminergic agonist with penile erectile effects but lacking the side effects of nausea and cardiovascular effects could be more efficacious. The effect of apomorphine on penile erection is not mediated by D₂-selective agonists (Hsieh et al., 2004). The recent report of a selective D₄ agonist that facilitates penile erection in rats indicates the dopamine D₄ receptor may play a physiological role in erection (Brioni et al., 2003).

Two other agents that induce penile erection by CNS mechanisms are -melanocyte-stimulating hormone (-MSH) and oxytocin. In conscious rats, i.c.v. administered -MSH and oxytocin induced intracavernosal pressure increases and penile erections whereas only oxytocin had an effect intrathecally (Mizusawa et al., 2002). This suggests that supraspinal -MSH and supraspinal and spinal oxytocin receptors are involved in this process. The -MSH peptide agonist Melanotan-II has been shown to effectively induce penile erection in humans in a limited clinical trial (Moreland et al., 2001b). A slightly different peptide has been prepared and has also been found to induce penile erection via central and spinal melanocortin receptors (Wessells et al., 2003). This concept has further been developed to the -MSH agonist PT-141, which will be dosed intranasally and is entering early stage clinical trials (Molinoff et al., 2003). Melanotan-II is a nonselective agonist reacting with four of the five melanocortin receptors. Small molecule, nonpeptide agonists of the melanocortin MC-4 receptor such as THIQ also induce penile erection and may provide a novel means of selective therapy via this pathway but remain in the preclinical stage (Van der Ploeg et al., 2002).

	Future Prospects

Top Abstract Incontinence Benign Prostatic Hyperplasia Male Erectile Dysfunction Future Prospects References

 
Incontinence remains a condition with few pharmacologic treatment options. Although having limited efficacy, muscarinic antagonists remain the mainstay of UUI therapy. The recent FDA approval of darifenacin allows testing of the hypothesis that M₃-selective antagonists will be more effective than nonselective agents such as oxybutynin and tolteridine. Preclinically, a critical examination of afferent blockade with new purinergic and tachykinin antagonists may be possible. Although K-ATP channel blockers directly relax bladder smooth muscle to relieve UUI, the challenge of achieving uroselectivity over cardiovascular effects in a clinical situation remains to be achieved.

With the recent FDA approval letter for duloxetine for SUI, this serotonin, norepinephrine-selective reuptake inhibitor has the potential to be one of the first pharmacologic options for the treatment of SUI other than collagen injections, surgery, and -adrenergic agonists. This particular area is ripe for exploration of other drug targets and therapeutic agents as well as a better understanding of serotonergic neurotransmission and SUI mechanisms.

In the treatment of MED, PDE5 inhibitors are the current pharmacological gold standard. Guanylate cyclase activators are an exciting means of taking advantage of the NO-cGMP mechanism but remain in preclinical development (Bischoff et al., 2003; Miller et al., 2003). These agents amplify the effects of endogenous NO while lacking some of the potential cardiovascular risks of PDE5 blockade (Brioni et al., 2002). Prostaglandin E vasodilation remains one of the more effective peripherally induced means of potentiating erection in a wide range of patients but is complicated by a more invasive means of delivery and pain in some patients (e.g., intracorporal injection or intraurethral administration). Whereas the recent characterization of EP receptor subtypes suggests that EP2 may play a major role in regulation of PGE-mediated, cAMP-based relaxation may open the way for orally bioavailable, selective agonists (Moreland et al., 2001a,b), localization of EP2 in the peripheral vasculature and in the gastrointestinal tract may preclude systemic dosing. One of the more exciting findings in the last several years has been the regulation of penile vasoconstrictive pathways via Rho kinase and the proof of principle that the Rho kinase inhibitor Y-28967 can mediate erection, but these agents also remain in preclinical development (Chitaley et al., 2003).

CNS activators are an exciting prospect, but may be complicated by potential side effect issues such as mild nausea with apomorphine and increased libido with Melanotan-II (Moreland et al., 2001b). The availability of a safe and efficacious oral CNS activating agent would provide not only novel therapy but may provide a means of combination therapies with PDE5 inhibitors in patients who have up to now been difficult to treat.

Although there have been a number advances in the treatment of LUTD in the last decade, much progress remains to be made. The future is bright with a number of potential drug targets now having small molecules to provide proof of principle and other targets at later stages with drugs to be tested in early phase clinical trials.

	Footnotes

 
ABBREVIATIONS. LUTD, lower urinary tract disorder; BPH, benign prostatic hyperplasia; CGRP, calcitonin gene-related peptide; CNS, central nervous system; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; 5-HT, 5-hydroxytryptamine; ET, endothelin; FDA, U.S. Food and Drug Administration; LUTS, lower urinary tract symptoms; MED, male erectile dysfunction; mAChR, muscarinic acetylcholine receptors; -MSH, -melanocyte-stimulating hormone; NO, nitric oxide; PACAP, pituitary adenylate cyclase-activating polypeptide; PDE, phosphodiesterase; PGE, prostaglandin E; sGC, soluble guanylate cyclase; SUI, stress urinary incontinence; UUI, urge urinary incontinence; VIP, vasoactive intestinal peptide; A-278637, (–)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide; A-350619, 3-[2-(4-chlorophenylsulfanyl)phenyl]-N-(4-dimethylaminobutyl)acrylamide]; ABT-866, N-[3-(1H-imidazol-4-ylmethyl)phenyl] ethanesulfonamide; BAY41-2272, 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine; BMS-193884, 3-(N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide; NAD-299, (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate; SR48968, (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenylbutyl] benzamide; TAK-637, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1,7]naphthyridine-6,13-dione; THIQ, N-[(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-2-oxoethylamine; WAY100635, N-(2-(1-(4-(2-methoxyphenyl)piperazin-yl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride; WAY133537, 1,2-diaminocyclobutene-3,4-dione((R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile; Y-27632, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide; ZD6169, N-(4-benzoylphenyl)-3,3,3-trifluro-2-hydroxy-2-methylpropionamine.

DOI: 10.1124/jpet.102.034991.

Address correspondence to: Dr. Robert B. Moreland, R4ND, Global Pharmaceutical Research and Development, AP9, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6118. E-mail: Robert.moreland{at}abbott.com

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