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Anticholinergic therapy for overactive bladder: A nicotinic modality?
Medical Hypotheses 81 (2013) 456–458
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Anticholinergic therapy for overactive bladder: A nicotinic modality? Steven M. Toler a,⇑, Daniel Yohannes b, Patrick M. Lippiello a, Michael B. Chancellor c a
Department of Clinical Pharmaceutical Sciences, Targacept, Inc., Winston-Salem, NC 27101, United States Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States c Department of Urology, William Beaumont Hospital, Royal Oak, MI 48073, United States b
a r t i c l e
i n f o
Article history: Received 16 April 2013 Accepted 11 June 2013
a b s t r a c t Until recently the treatment of Overactive Bladder (OAB) has primarily been aimed at mitigating hypercholinergic activity in the bladder via antagonism of muscarinic acetylcholine receptors. However, antimuscarinic therapies have limited efficacy and significant side effects. It is now known that nicotinic acetylcholine receptor (nAChR) subtypes are expressed in the urothelium and on afferent nerve fibers in the bladder, and it is believed that these receptors serve to communicate urgency and facilitate voiding function. This presents the opportunity for an alternative to the antimuscarinic approach, one which involves inhibition of nAChRs in the bladder that are chronically overstimulated by acetylcholine. Specifically, we hypothesize that an orally administered nAChR-selective inhibitor with extensive renal elimination will result in higher local concentrations in the bladder and lower systemic exposure than current therapies, representing a novel targeted approach to the treatment of OAB with a more favorable side effect profile. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Overactive bladder – unmet medical need As defined by the International Continence Society (ICS), Overactive Bladder (OAB) is a chronic urological condition characterized by lower urinary tract symptoms, including: urinary urgency with or without urge incontinence, urinary frequency and nocturia, and absence of causative infection or pathologic conditions, suggestive of underlying detrusor over-activity (phasic increases in detrusor pressure) [1]. In the United States, the incidence of OAB among men and women is similar (16.0% vs. 16.9%, respectively); however, women demonstrate a higher incidence of urge incontinence [2]. The prevalence of overactive bladder increases with advancing age and affects about 16% of adults over 40 [3]. Of these, about 30% suffer from urge incontinence, called ‘‘wet OAB,’’ with profound reduction in quality of life [3,4]. The other 70% have what is known as ‘‘dry OAB,’’ which is also a debilitating condition and is likely to progress to incontinence. Antimuscarinic drugs currently are the first-line pharmacotherapy for treating overactive bladder. None of these antimuscarinic drugs is completely selective for the bladder. They also produce adverse effects of constipation and dry mouth. Most of these agents are extensively metabolized by the liver, with only a ⇑ Corresponding author. Address: Targacept, Inc., 100 N. Main St., Ste 1510, Winston-Salem, NC 27101, United States. Tel.: +1 336 480 2187; fax: +1 336 480 2107. E-mail address: [email protected] (S.M. Toler). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.06.008
fraction of the administered dose excreted as unchanged drug. This limits the ability of these agents to selectively target receptors in the bladder urothelium while sparing interactions with systemic muscarinic receptors. New drugs with better efficacy and greater bladder selectivity are needed. Role of hyper-cholinergic tone in OAB The most common treatment for OAB is the use of anti-muscarinic agents which inhibit muscarinic acetylcholine receptors (mAChRs) in the bladder detrusor muscle that are stimulated by acetylcholine (ACh) released from parasympathetic nerves, thereby inhibiting voiding contractions [5]. Basal release of ACh from the bladder urothelium increases with age and bladder stretch, suggesting that locally increased ACh levels in the bladder may induce OAB [6]. Until the recent development of b3-adrenergic agonists for treating OAB, the therapeutic focus had been primarily on mAChRs present in the urothelium as well as in the detrusor, the M2 and M3 subtypes being predominant [7]. However, in the past decade our understanding of the role of nicotinic acetylcholine receptors in bladder function suggests that they may represent novel therapeutic targets for OAB. Nicotinic cholinergic pharmacology and bladder function Nicotinic acetylcholine receptors (nAChRs) are prototypical ligand-gated ion channels that allow the passage of Na+, K+ and Ca++ in and out of cells following activation by acetylcholine. This family of receptors has long been known to serve many
S.M. Toler et al. / Medical Hypotheses 81 (2013) 456–458
457
physiological roles throughout the body. In particular they are the primary receptors responsible for synaptic transmission in autonomic ganglia and skeletal muscle [8]. Structurally, mammalian nAChRs are composed of five protein subunits arranged like staves in a barrel around a central ion pore, drawing from different combinations of 17 subunits (a1–7, a9, a10, b1–4, c, d, and e). In neuronal nAChRs the five subunits can all be the same (e.g., a75), can consist of one type of a-subunit and one type of b-subunit (e.g., a32b43), or can contain three or more different subunits (e.g., a32a5b42). Each type of receptor has different electrophysiological and pharmacological properties which have been hypothesized to be responsible for the widely varying effects of ACh across tissues. nAChRs in the urothelium The afferent nerves in the urinary bladder respond to a variety of stimuli including distension and contraction of the detrusor muscle as well as noxious chemicals contained in the urine or released during infection. It has been suggested that the epithelial layer of the bladder (urothelium) may influence afferent nerve activity by expressing neuronal-like properties, including the release of neurotransmitters such as ACh, nitric oxide (NO) and ATP as well as influencing the sensitivity to these transmitters [9]. These transmitters are believed to act on afferent nerve terminals in the bladder wall to influence bladder activity, including voiding and urine storage reflexes. The release of these transmitters may be modulated in part by nAChRs. The localization and functional properties of nAChRs have been studied in rat urothelium [10]. One important nAChR subtype, located primarily in the umbrella cells adjacent to the bladder lumen, is a heteromeric a3⁄ nAChR (where a3⁄ denotes a combination of a3 subunits plus one or more unidentified subunits from those expressed in the tissue, e.g., a5, b3 and b4), which has an excitatory effect on bladder reflexes [10]. Stimulation of urothelial a3⁄ nAChRs through intravesical administration of selective agonists was found to significantly alter functional voiding and to modulate the release of ATP [11]. Thus the activation of a3⁄ nAChRs in rat urothelium appears to be linked to ATP-mediated stimulation of micturition reflexes by purinergic receptors on afferent nerves. The presence of a3, a5, b3 and b4 nAChR subunit mRNA in human bladder urothelial cells has also been reported [12] and there is a wide distribution of a3-containing nAChRs in ganglion, smooth muscle and epithelial cells in other tissues obtained from normal healthy subjects [13], suggesting that this subtype may also be expressed in human bladder epithelium. nAChRs on bladder afferent nerves It has been demonstrated that nAChRs are present in nociceptive, sensory neurons and that nicotine can induce inward currents in rat dorsal root ganglion (DRG) afferents [14]. A very recent publication has also described the expression of nAChR mRNA in bladder sensory afferent nerves of mice [15]. Of interest, the a3containing nAChR is highly expressed. Approximately 69% of the neurons express this subtype, indicating organ selectivity in projections of a3 nAChR subunit positive sensory neurons and a particular relevance of this subunit in regulating bladder function [15]. It has been demonstrated in rats that nAChR-mediated C-fiber sensitization mechanisms are present in the bladder to induce bladder overactivity [16]. Taken together, these studies raise the possibility that nAChRs in C-fiber bladder afferent pathways are involved in OAB pathogenesis.
Fig. 1. Diagram of hypothesis – delivery of high concentrations of an a3⁄ nAChR inhibitor (INH) to the bladder should effectively reduce overactive afferent signaling and urge to void by inhibiting a3⁄ receptor activity. Shown are a3⁄ nAChRs in the bladder urothelium where they are believed to be activated by stretch-induced ACh release [11], and in turn to elicit urgency and voiding signals, either by triggering release of ATP onto purinergic receptors on afferent nerves [11] or possibly by direct depolarization of afferent nerve fibers [15] (ACh = acetylcholine; P2X⁄ = purinergic receptors).
pharmacokinetics that favor delivery of high concentrations to the bladder that we hypothesize will effectively reduce bladder hyperactivity caused by overactivity of an a3⁄-linked ATP-driven excitatory pathway in the bladder urothelium and/or reduce increased urgency and voiding caused by overactivity of a3⁄ nAChRs on bladder afferent sensory nerves (see Fig. 1). Evidence supporting the hypothesis Hexamethonium is a non-competitive blocker of nAChRs [17]. It does not directly affect muscarinic acetylcholine receptors (mAChRs) located on target organs of the parasympathetic nervous system [18], but acts as an antagonist at a3-containing nAChRs located in sympathetic and parasympathetic ganglia [19]. Following intravesical administration in rodents, hexamethonium significantly blocks bladder contractions at concentrations of 1–10 lM [10]. Since hexamethonium is a cation, it is unlikely to penetrate the umbrella cells of the urothelium to reach the bladder smooth muscle or C-fiber afferent sensory nerves. Therefore, these effects have been suggested to occur via inhibition of the a3⁄ nAChRs expressed at the luminal surface of the urothelium [10]. This indicates that delivery of a3⁄ nAChR inhibitors to the interior of the bladder at sufficient concentration can significantly reduce bladder activity. Studies with intravesically administered a3⁄ agonists such as epibatidine [10] suggest that a3⁄ nAChRs on C-fiber afferents can also be activated to produce increased bladder pressure. Thus it should be feasible to block these receptors with a selective inhibitor and reduce ACh-induced sensations of fullness and urgency. Testing the hypothesis An inhibitor of a3⁄ nAChRs with good oral bioavailability, low oxidative metabolism and extensive renal excretion would appear
The hypothesis We propose an alternative, anticholinergic approach to treat OAB: an orally administered a3⁄ nAChR inhibitor with
Fig. 2. Structure of dexmecamylamine (also known as TC-5214).
458
S.M. Toler et al. / Medical Hypotheses 81 (2013) 456–458
to be an ideal agent to target both urothelial and underlying C-fiber associated nAChRs and produce benefit in treating OAB, with fewer systemic side effects. We intend to test this hypothesis with a clinical study of dexmecamylamine (Fig. 2) in subjects with OAB. Dexmecamylamine is a highly potent nicotinic channel modulator that produces usedependent inhibition of nAChRs, including a3⁄ nAChRs. Unlike hexamethonium, which has poor oral bioavailability (<1%), greater than 90% of an administered oral dose of dexmecamylamine is eliminated unchanged in the bladder, thus preferentially targeting the urothelium. Daily doses of 4 mg of dexmecamylamine have been well-tolerated in previous clinical trials, producing low rates of anticholinergic side effects (e.g., dry mouth). These low oral doses of dexmecamylamine produce systemic concentrations below 100 nM, yet produce mean urine concentrations in excess of 10 lM, providing an approximately 200-fold urine to plasma ratio. In rodents, similar urinary concentrations of hexamethonium (10 lM) have produced significant increases in the inter-contraction interval and bladder volume, a decrease in micturition frequency and no change in the amplitude of bladder contractions. In this regard, mecamylamine (racemate containing 50% dexmecamylamine) has been shown to block nAChRs with 10-fold higher potency than hexamethonium in electrophysiological studies with ganglionic preparations [20]. We believe the properties of dexmecamylamine, if translated successfully in the clinic, would represent a compelling profile for the treatment of OAB. Conclusions While the precise molecular targets associated with effects on the bladder are still under investigation, dexmecamylamine functionally interacts with human a3-containing nicotinic receptors [21]. Inhibition of a3⁄ nAChR hyperactivity in the urothelial cells by dexmecamylamine is hypothesized to inhibit the ATP driven excitatory pathway (described above), thereby lowering bladder hyperactivity. The additional inhibition of a3⁄ nAChRs on bladder afferent nerve endings is hypothesized to further reduce the sense of urgency and bladder voiding reflexes. Since the inhibition of receptor function by dexmecamylamine occurs by a use-dependent mechanism, the amount of inhibition will be directly proportional to the level of receptor activity or, in the case of OAB, hyperactivity. This mechanism suggests that dexmecamylamine could normalize receptor (and bladder) function but avoid overinhibiting normal function. Conflict of interest SMT and PML are employees and stockholders of Targacept, Inc.; DY is a stockholder of Targacept, Inc.; MBC is a consultant to Targacept, Inc.
References [1] Abrams P, Cardozo I, Fall M, et al. The standardization of terminology of lower urinary tract function: report from the standardization sub-committee of the international continence society. Neurourol Urodyn 2002;21:167–78. [2] Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20:27–336. [3] Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001;87:760–6. [4] Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. Br Med J 2003;326:841–4. [5] de Groat WC, Yoshimura N. Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury. Prog Brain Res 2006;152:59–84. [6] Yoshida M, Miyamae K, Iwashita H, Otani M, Inadome A. Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology 2004;63:17. [7] Matsumoto Y, Miyazato M, Furuta A, Torimoto K, Hirao Y, Chancellor MB, et al. Differential roles of M2 and M3 muscarinic receptor subtypes in modulation of bladder afferent activity in rats. Urology 2010;75:862–7. [8] De Biasi M. Nicotinic mechanisms in the autonomic control of organ systems. J Neurobiol 2002;53:568–79. [9] Andersson KE. Bladder activation: afferent mechanisms. Urology 2002;59:43–50. [10] Beckel JM, Kanai A, Lee SJ, de Groat WC, Birder LA. Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells. Am J Physiol Renal Physiol 2006;290:F103–10. [11] Beckel JM, Birder LA. Differential expression and function of nicotinic acetylcholine receptors in the urinary bladder epithelium of the rat. J Physiol 2012;590:1465–80. [12] Kim J, Beckel JM, Birder LA, Kiss S, Kanai A, Dineley K. Expression of nicotinic acetylcholine receptors in human bladder epithelial cells. Soc Neurosci Abstr 2001. 809.3. [13] Richardson CE, Morgan JM, Jasani B, et al. Megacystis–microcolon–intestinal hypoperistalsis syndrome and the absence of the alpha3 nicotinic acetylcholine receptor subunit. Gastroenterology 2001;121:350–7. [14] Haberberger RV, Bernardini N, Kress M, Hartmann P, Lips KS, Kummer W, et al. Nicotinic acetylcholine receptor subtypes in nociceptive dorsal root ganglion neurons of the adult rat. Auton Neurosci 2004;113:32. [15] Nandigama R, Ibañez-Tallon I, Lips KS, Schwantes U, Kummer W, Bschleipfer T. Expression of nicotinic acetylcholine receptor subunit mRNA in mouse bladder afferent neurons. Neuroscience 2013;229:27–35. [16] Masuda H, Hayashi Y, Chancellor MB, Kihara K, de Groat WC, de Miguel F, et al. Roles of peripheral and central nicotinic receptors in the micturition reflex in rats. J Urol 2006;176:374–9. [17] Paton WDM. Ganglionic blocking agents: with special reference to the effect of hexamethonium on the cardiovascular system. Br Med Bull 1952;8:310–5. [18] Eglen RM, Michel AD, Cornett CM, Kunysz EA, Whiting RL. The interaction of hexamethonium with muscarinic receptor subtypes in vitro. Br J Pharmacol 1989;98:499–506. [19] Howland RD, Mycek MJ. In: Harvey RA, Champe PC, editors. Lippincott’s Illustrated Reviews: Pharmacology. third ed. Lippincott’s; 2006. p. 47. [20] Liu W, Zheng JQ, Liu ZW, Li LJ, Wan Q, Liu CG. Difference in action sites between mecamylamine and hexamethonium on nicotinic receptors of sympathetic neurons. Acta Physiologica Sinica 2002;54:497–500. [21] Papke RL, Sanberg PR, Shytle RD. Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes. J Pharmacol Exp Ther 2001;297:646–56.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Anticholinergic therapy for overactive bladder: A nicotinic modality? Steven M. Toler a,⇑, Daniel Yohannes b, Patrick M. Lippiello a, Michael B. Chancellor c a
Department of Clinical Pharmaceutical Sciences, Targacept, Inc., Winston-Salem, NC 27101, United States Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States c Department of Urology, William Beaumont Hospital, Royal Oak, MI 48073, United States b
a r t i c l e
i n f o
Article history: Received 16 April 2013 Accepted 11 June 2013
a b s t r a c t Until recently the treatment of Overactive Bladder (OAB) has primarily been aimed at mitigating hypercholinergic activity in the bladder via antagonism of muscarinic acetylcholine receptors. However, antimuscarinic therapies have limited efficacy and significant side effects. It is now known that nicotinic acetylcholine receptor (nAChR) subtypes are expressed in the urothelium and on afferent nerve fibers in the bladder, and it is believed that these receptors serve to communicate urgency and facilitate voiding function. This presents the opportunity for an alternative to the antimuscarinic approach, one which involves inhibition of nAChRs in the bladder that are chronically overstimulated by acetylcholine. Specifically, we hypothesize that an orally administered nAChR-selective inhibitor with extensive renal elimination will result in higher local concentrations in the bladder and lower systemic exposure than current therapies, representing a novel targeted approach to the treatment of OAB with a more favorable side effect profile. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Overactive bladder – unmet medical need As defined by the International Continence Society (ICS), Overactive Bladder (OAB) is a chronic urological condition characterized by lower urinary tract symptoms, including: urinary urgency with or without urge incontinence, urinary frequency and nocturia, and absence of causative infection or pathologic conditions, suggestive of underlying detrusor over-activity (phasic increases in detrusor pressure) [1]. In the United States, the incidence of OAB among men and women is similar (16.0% vs. 16.9%, respectively); however, women demonstrate a higher incidence of urge incontinence [2]. The prevalence of overactive bladder increases with advancing age and affects about 16% of adults over 40 [3]. Of these, about 30% suffer from urge incontinence, called ‘‘wet OAB,’’ with profound reduction in quality of life [3,4]. The other 70% have what is known as ‘‘dry OAB,’’ which is also a debilitating condition and is likely to progress to incontinence. Antimuscarinic drugs currently are the first-line pharmacotherapy for treating overactive bladder. None of these antimuscarinic drugs is completely selective for the bladder. They also produce adverse effects of constipation and dry mouth. Most of these agents are extensively metabolized by the liver, with only a ⇑ Corresponding author. Address: Targacept, Inc., 100 N. Main St., Ste 1510, Winston-Salem, NC 27101, United States. Tel.: +1 336 480 2187; fax: +1 336 480 2107. E-mail address: [email protected] (S.M. Toler). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.06.008
fraction of the administered dose excreted as unchanged drug. This limits the ability of these agents to selectively target receptors in the bladder urothelium while sparing interactions with systemic muscarinic receptors. New drugs with better efficacy and greater bladder selectivity are needed. Role of hyper-cholinergic tone in OAB The most common treatment for OAB is the use of anti-muscarinic agents which inhibit muscarinic acetylcholine receptors (mAChRs) in the bladder detrusor muscle that are stimulated by acetylcholine (ACh) released from parasympathetic nerves, thereby inhibiting voiding contractions [5]. Basal release of ACh from the bladder urothelium increases with age and bladder stretch, suggesting that locally increased ACh levels in the bladder may induce OAB [6]. Until the recent development of b3-adrenergic agonists for treating OAB, the therapeutic focus had been primarily on mAChRs present in the urothelium as well as in the detrusor, the M2 and M3 subtypes being predominant [7]. However, in the past decade our understanding of the role of nicotinic acetylcholine receptors in bladder function suggests that they may represent novel therapeutic targets for OAB. Nicotinic cholinergic pharmacology and bladder function Nicotinic acetylcholine receptors (nAChRs) are prototypical ligand-gated ion channels that allow the passage of Na+, K+ and Ca++ in and out of cells following activation by acetylcholine. This family of receptors has long been known to serve many
S.M. Toler et al. / Medical Hypotheses 81 (2013) 456–458
457
physiological roles throughout the body. In particular they are the primary receptors responsible for synaptic transmission in autonomic ganglia and skeletal muscle [8]. Structurally, mammalian nAChRs are composed of five protein subunits arranged like staves in a barrel around a central ion pore, drawing from different combinations of 17 subunits (a1–7, a9, a10, b1–4, c, d, and e). In neuronal nAChRs the five subunits can all be the same (e.g., a75), can consist of one type of a-subunit and one type of b-subunit (e.g., a32b43), or can contain three or more different subunits (e.g., a32a5b42). Each type of receptor has different electrophysiological and pharmacological properties which have been hypothesized to be responsible for the widely varying effects of ACh across tissues. nAChRs in the urothelium The afferent nerves in the urinary bladder respond to a variety of stimuli including distension and contraction of the detrusor muscle as well as noxious chemicals contained in the urine or released during infection. It has been suggested that the epithelial layer of the bladder (urothelium) may influence afferent nerve activity by expressing neuronal-like properties, including the release of neurotransmitters such as ACh, nitric oxide (NO) and ATP as well as influencing the sensitivity to these transmitters [9]. These transmitters are believed to act on afferent nerve terminals in the bladder wall to influence bladder activity, including voiding and urine storage reflexes. The release of these transmitters may be modulated in part by nAChRs. The localization and functional properties of nAChRs have been studied in rat urothelium [10]. One important nAChR subtype, located primarily in the umbrella cells adjacent to the bladder lumen, is a heteromeric a3⁄ nAChR (where a3⁄ denotes a combination of a3 subunits plus one or more unidentified subunits from those expressed in the tissue, e.g., a5, b3 and b4), which has an excitatory effect on bladder reflexes [10]. Stimulation of urothelial a3⁄ nAChRs through intravesical administration of selective agonists was found to significantly alter functional voiding and to modulate the release of ATP [11]. Thus the activation of a3⁄ nAChRs in rat urothelium appears to be linked to ATP-mediated stimulation of micturition reflexes by purinergic receptors on afferent nerves. The presence of a3, a5, b3 and b4 nAChR subunit mRNA in human bladder urothelial cells has also been reported [12] and there is a wide distribution of a3-containing nAChRs in ganglion, smooth muscle and epithelial cells in other tissues obtained from normal healthy subjects [13], suggesting that this subtype may also be expressed in human bladder epithelium. nAChRs on bladder afferent nerves It has been demonstrated that nAChRs are present in nociceptive, sensory neurons and that nicotine can induce inward currents in rat dorsal root ganglion (DRG) afferents [14]. A very recent publication has also described the expression of nAChR mRNA in bladder sensory afferent nerves of mice [15]. Of interest, the a3containing nAChR is highly expressed. Approximately 69% of the neurons express this subtype, indicating organ selectivity in projections of a3 nAChR subunit positive sensory neurons and a particular relevance of this subunit in regulating bladder function [15]. It has been demonstrated in rats that nAChR-mediated C-fiber sensitization mechanisms are present in the bladder to induce bladder overactivity [16]. Taken together, these studies raise the possibility that nAChRs in C-fiber bladder afferent pathways are involved in OAB pathogenesis.
Fig. 1. Diagram of hypothesis – delivery of high concentrations of an a3⁄ nAChR inhibitor (INH) to the bladder should effectively reduce overactive afferent signaling and urge to void by inhibiting a3⁄ receptor activity. Shown are a3⁄ nAChRs in the bladder urothelium where they are believed to be activated by stretch-induced ACh release [11], and in turn to elicit urgency and voiding signals, either by triggering release of ATP onto purinergic receptors on afferent nerves [11] or possibly by direct depolarization of afferent nerve fibers [15] (ACh = acetylcholine; P2X⁄ = purinergic receptors).
pharmacokinetics that favor delivery of high concentrations to the bladder that we hypothesize will effectively reduce bladder hyperactivity caused by overactivity of an a3⁄-linked ATP-driven excitatory pathway in the bladder urothelium and/or reduce increased urgency and voiding caused by overactivity of a3⁄ nAChRs on bladder afferent sensory nerves (see Fig. 1). Evidence supporting the hypothesis Hexamethonium is a non-competitive blocker of nAChRs [17]. It does not directly affect muscarinic acetylcholine receptors (mAChRs) located on target organs of the parasympathetic nervous system [18], but acts as an antagonist at a3-containing nAChRs located in sympathetic and parasympathetic ganglia [19]. Following intravesical administration in rodents, hexamethonium significantly blocks bladder contractions at concentrations of 1–10 lM [10]. Since hexamethonium is a cation, it is unlikely to penetrate the umbrella cells of the urothelium to reach the bladder smooth muscle or C-fiber afferent sensory nerves. Therefore, these effects have been suggested to occur via inhibition of the a3⁄ nAChRs expressed at the luminal surface of the urothelium [10]. This indicates that delivery of a3⁄ nAChR inhibitors to the interior of the bladder at sufficient concentration can significantly reduce bladder activity. Studies with intravesically administered a3⁄ agonists such as epibatidine [10] suggest that a3⁄ nAChRs on C-fiber afferents can also be activated to produce increased bladder pressure. Thus it should be feasible to block these receptors with a selective inhibitor and reduce ACh-induced sensations of fullness and urgency. Testing the hypothesis An inhibitor of a3⁄ nAChRs with good oral bioavailability, low oxidative metabolism and extensive renal excretion would appear
The hypothesis We propose an alternative, anticholinergic approach to treat OAB: an orally administered a3⁄ nAChR inhibitor with
Fig. 2. Structure of dexmecamylamine (also known as TC-5214).
458
S.M. Toler et al. / Medical Hypotheses 81 (2013) 456–458
to be an ideal agent to target both urothelial and underlying C-fiber associated nAChRs and produce benefit in treating OAB, with fewer systemic side effects. We intend to test this hypothesis with a clinical study of dexmecamylamine (Fig. 2) in subjects with OAB. Dexmecamylamine is a highly potent nicotinic channel modulator that produces usedependent inhibition of nAChRs, including a3⁄ nAChRs. Unlike hexamethonium, which has poor oral bioavailability (<1%), greater than 90% of an administered oral dose of dexmecamylamine is eliminated unchanged in the bladder, thus preferentially targeting the urothelium. Daily doses of 4 mg of dexmecamylamine have been well-tolerated in previous clinical trials, producing low rates of anticholinergic side effects (e.g., dry mouth). These low oral doses of dexmecamylamine produce systemic concentrations below 100 nM, yet produce mean urine concentrations in excess of 10 lM, providing an approximately 200-fold urine to plasma ratio. In rodents, similar urinary concentrations of hexamethonium (10 lM) have produced significant increases in the inter-contraction interval and bladder volume, a decrease in micturition frequency and no change in the amplitude of bladder contractions. In this regard, mecamylamine (racemate containing 50% dexmecamylamine) has been shown to block nAChRs with 10-fold higher potency than hexamethonium in electrophysiological studies with ganglionic preparations [20]. We believe the properties of dexmecamylamine, if translated successfully in the clinic, would represent a compelling profile for the treatment of OAB. Conclusions While the precise molecular targets associated with effects on the bladder are still under investigation, dexmecamylamine functionally interacts with human a3-containing nicotinic receptors [21]. Inhibition of a3⁄ nAChR hyperactivity in the urothelial cells by dexmecamylamine is hypothesized to inhibit the ATP driven excitatory pathway (described above), thereby lowering bladder hyperactivity. The additional inhibition of a3⁄ nAChRs on bladder afferent nerve endings is hypothesized to further reduce the sense of urgency and bladder voiding reflexes. Since the inhibition of receptor function by dexmecamylamine occurs by a use-dependent mechanism, the amount of inhibition will be directly proportional to the level of receptor activity or, in the case of OAB, hyperactivity. This mechanism suggests that dexmecamylamine could normalize receptor (and bladder) function but avoid overinhibiting normal function. Conflict of interest SMT and PML are employees and stockholders of Targacept, Inc.; DY is a stockholder of Targacept, Inc.; MBC is a consultant to Targacept, Inc.
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