Emerging drugs for the treatment of bladder storage dysfunction

ABSTRACT

Introduction

Current drug treatment of lower urinary tract disorders, for example, overactive bladder syndrome and lower urinary tract symptoms associated with benign prostatic hyperplasia, is moderately effective, has a low treatment persistence and some short- and long-term adverse events. Even if combination therapy with approved drugs may offer advantages in some patients, there is still a need for new agents.

Areas covered

New b₃-adrenoceptor agonists, antimuscarinics, the naked Maxi-K channel gene, a novel 5HT/NA reuptake inhibitor and soluble guanylate cyclase activators are discussed. Focus is given to P2X3 receptor antagonists, small molecule blockers of TRP channels, the roles of cannabis on incontinence in patients with multiple sclerosis, and of drugs acting directly on CB1 and CB2 receptor or indirectly via endocannabinoids by inhibition of fatty acid aminohydrolase.

Expert opinion

New potential alternatives to currently used drugs/drug principles are emerging, but further clinical testing is required before they can be evaluated as therapeutic alternatives. It seems that for the near future individualized treatment with approved drugs and their combinations will be the prevailing therapeutic approach.

KEYWORDS:

• Cannabinoids
• overactive bladder
• lower urinary tract symptoms
• P2X3 receptor antagonists
• sGC activators
• TRP channel blockers

1. Background and medical need

Bladder dysfunction, for example, the overactive bladder (OAB) syndrome and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and neurogenic bladder, continues to offer a therapeutic challenge. As stated by Abreu-Mendez et al. [1] the main problems with pharmacotherapy for these disorders are moderate efficacy, low persistence on treatment, and the incidence of short- and long-term adverse events (AE) associated with some compounds. As is evident from the extensive review of Peyronnet et al. [2], there are several subtypes of OAB, and it is difficult to identify the underlying pathology/pathophysiology in most patients. This implies that there are many possible targets and opportunities for drugs/drug principles to exert at least a moderate, beneficial effect in individual patients. A logical way to improve treatment would be combination therapy with approved drugs [see, e.g., 3–5], and this seems to be a promising option for those who do not experience sufficient benefit with monotherapy. This add-on scenario offers the possibility to have a more tailored approach to the management of OAB and LUTS, always seeking the optimal balance between efficacy and tolerability for a given patient [4]. However, combination therapy may not be a final, satisfactory solution of the problem. Dahm et al. [6], performing a systematic review and meta-analysis, evaluated whether newer drugs (e.g. mirabegron and tadalafil) for the treatment of LUTS offered advantages over established treatments, primarily older a₁-adrenoceptor antagonists (i.e. tamsulosin, alfuzosin, doxazosin), either as monotherapy or in combination. They found that none of the drugs or drug combinations newly used to treat LUTS were more effective compared to monotherapy with older a₁-adrenoceptor antagonist. In addition, adverse effects with newer treatments or combinations were similar or greater than those for older a₁-adrenoceptor antagonist monotherapy when evidence was sufficient to assess. Even if combination therapy with existing drugs may offer advantages in some patients, this may not satisfy all and there is still a need for new agents that can help the patients who do not respond to currently available options [1,4]. In this review, focus is given to drugs and drug principles that may have a potential to be developed into new, clinically useful alternatives (Table 1).

Table 1. Emerging drugs for treatment of urine storage disorders, LUTD = Lower Urinary Tract Dysfunction.

Target	Compound	Examined in humans	Limitations
β3-adrenoceptor	Solabegron	Phase 2	Still in pipeline
β3-adrenoceptor	Ritobegron	Phase 2	Still in pipeline?
Muscarinic receptors	Tarafenacin	Phase 2	Long-term risks
Muscarinic receptors	DA-8010	Phase 3	Long-term risks
Muscarinic receptors	Afacifenacin	Phase 2	Long-term risks
Serotonin uptake	Litoxetine	Phase 2	Efficacy?
NK1 receptor	Serlopitant	Phase 2	Low efficacy
Tachykinin release	Cizorlitine	Phase 2	Low efficacy
Vitamin D3 receptor	Elocalcitol	Phase2	Development stopped
P2X3 receptor	Gefapixant	Phase 3 (not LUTD indication)	Only proof of concept for LUTD
P2X3 receptor	Eliapixant	Phase 3 (not LUTD indication)	Not tested for LUTD
TRPV1	SB-705498; AMG-517; AZD1386; PHE3779; XEN-D0501	Phase1	Hyperthermia
TRPA1	GRC-17356	Phase 2	Still in development
TRPV4	GSK-2798745	Phase 2 (not LUTD indication)	Not tested for LUTD
TRM8	PF-05105679	Phase 1	Adverse effects
FAAH	ASP-3652	Phase 2	Still in development
Cannabinoid receptors	THC, dronabinol, nabilone, cannabidiol	Phase 3 for dronabinol, nabilone, cannabidiol (not LUTD indication)	THC approved for MS only
Maxi K-channel	URO-902	Phase 2	Still in development
sGC	Cinaciquat	Phase 2 (not LUTD indication)	In development

2. Existing treatments and new additions to established principles

Over the last five years, the effects of currently used drugs for treatment of OAB and LUTS have been extensively reviewed [1,5,7–10]. These drugs target prostate growth, a₁-adrenoceptors, muscarinic receptors, b₃-adrenoceptors, afferent and efferent neurotransmission, and phosphodiesterase enzymes, and include 5a-reductase inhibitors, selective a₁-adrenoceptor antagonists, muscarinic receptor antagonists, b₃-adrenoceptor agonists, botulinum toxin, PDE5 inhibitors, and various combinations of these drugs.

Some new additions of drugs acting on these established targets are in the pipeline, but have still not reached the clinic, for example, the b₃-receptor agonists solabegron and ritobegron. The development of ritobegron has apparently been stopped. A phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study including 406 female subjects with OAB has been completed, but the results have not yet been published [11]. The antimuscarinic tarafenacin (SVT-40776), a quinuclidinol derivative, was reported to have the highest selectivity for human M3 vs M2 subtype of any other reference antagonists tested [12]. The clinical effects and safety of the drug were tested in a randomized, double-blind, placebo-controlled Phase II study, demonstrating a greater improvement than with placebo on OAB symptoms [13]. Further clinical studies of the drug do not seem to have been reported. Another antimuscarinic, DA-8010, is a novel, highly potent M₃ receptor antagonist experimentally shown to have high urinary bladder selectivity [14]. In a randomized, double-blind, human Phase II study, including a total of 306 patients (69.93% female) the drug (2.5 and 5 mg) was tested against an active reference group (solifenacin 5 mg), or placebo [15]. DA-8010 5 mg was significantly better than placebo and not different from solifenacin. No serious drug-related adverse events were observed in any patient. Afacifenacin (SMP-986) is a new anticholinergic agent whose mechanism of action consists of nonselective blockade of muscarinic receptors and blockade of sodium channels, leading to inhibition of afferent nerves. Clinical effects include a reduction in pollakiuria and urgency incontinence, and an increase in voiding volume; the drug was claimed to have a low incidence of side effects related to muscarinic receptor antagonism, such as dry mouth [16]. The results of a completed phase II randomized, double‐blind, placebo‐controlled clinical trial have apparently not yet been published.

Litoxetine, a serotonin reuptake inhibitor, was studied in two randomized, double‐blind, placebo‐controlled clinical trials for treatment of urinary incontinence and mixed urinary incontinence [17]. Litoxetine reduced the number of incontinence episodes per week compared to placebo, but there was an unexpectedly high placebo response, and therefore the drug did not meet the primary efficacy endpoint. However, 71% of participants reported a clinically meaningful improvement in the King’s Health Questionnaire.

Some compounds have shown promising results in phase II but this apparently did not lead to full clinical development programs. Examples include the NK₁ receptor antagonist serlopitant [18] the tachykinin release inhibitor cizolirtine [19,20], and the vitamin D₃ analogue, elocalcitol [21]. If any of these drugs/principles can be further developed to clinically useful alternatives for treatment of storage symptoms is presently unclear.

3. Drugs and drug classes/principles in development: research goals and scientific rationales

In a review from 2016 on potential future pharmacological treatments of OAB and LUTS, it was suggested that the most promising targets were to be found within the purinergic system, among the different members of the TRP channel family, and within the cannabinoid system [22]. Even if much new physiological/pathophysiological information on these potential targets has been accumulated, supporting a good rationale for treatment of LUT disorders, the progress in drug development has been slow and few drug candidates have emerged. The question may be raised if they still hold promise for future development.

3.1. Purinergic system – P2X3 receptor antagonists

3.1.1. Rationale

When the urothelium is stretched during bladder filling, ATP is released from the umbrella cells and stimulates purinergic receptors on suburothelial sensory nerves. Mechanotransduction pathways are activated that not only mediate the sensation of bladder filling and urgency but also initiates the voiding reflex [23,24]. P2X receptors are ligand-gated ion channels and seven P2X receptor subunits have been identified from molecular studies. They have all been characterized functionally and pharmacologically [25]. In the lamina propria, urothelium and detrusor smooth muscle of rat and human bladder, P2X3 and several other P2X receptors are expressed [26,27]. If the bladder is distended, an increased afferent nerve activity is initiated [28]. This activity is mimicked by ATP and/or α,β-meATP, suggesting a major sensory role for urothelially released ATP acting via P2X3 receptors on a subpopulation of pelvic afferent fibers. Pandita et al. [29] showed that intravesical infusion of ATP or α,β-meATP stimulated bladder overactivity in conscious rats. The effect was concentration-dependent and sensitive to the ATP receptor antagonist, TNP-ATP. Together these findings strongly suggest that P2X2/P2X3 receptors are important in sensing volume changes during normal bladder filling, and that they under pathophysiological conditions may participate in lowering the threshold for C-fiber activation.

In different LUT disorders, the purinergic signaling in the bladder may be changed [24,30], and for decades particularly P2X3 receptors have been the target for drugs intended for treatment of LUT disorders [31–33]. Selective P2X3 antagonists, such as A-317491, and AF-353, were shown to be effective in several animal models of bladder dysfunction, but not taken into clinical use. However, several novel P2X3 and P2X2/3 antagonist have been synthesized [34].

3.1.2. Emerging drugs

Results from a phase II clinical trial (NCT01569438) with the selective, orally administered P2X3 receptor antagonist gefapixant (AF-219, MK-7264, and RO-4926219) showed a significant (p = 0.034) reduction in urinary urgency and a positive trend in the improvement of pain in patients with IC/BPS [35]. This drug showed efficacy in patients with refractory chronic cough [36] and recently, further controlled studies confirmed its efficacy on this condition. It was well tolerated except for disturbances in taste perception [37–39]. Gefapixant is the first-in-class clinically developed antagonist for the P2X3 subtype of trimeric ionotropic purinergic receptors, showing nanomolar potency for the human P2X3 homotrimeric channel and essentially no activity at related channels devoid of P2X3 subunits [40]. Also, eliapixant (BAY 1817080) is a P2X3 receptor antagonist, which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3 [41–43]. Its efficay, safety, and tolerability in refractory chronic cough have been tested in randomized, double-blind phase I and II studies [42,43]. Eliapixant was shown to be well tolerated with a minimal effect on taste perception and with a long plasma half-life. Davenport et al [41]. studied the effects of the drug on disorders associated with hypersensitive nerve fibers in different relevant rodent models. They showed that the drug reduced inflammatory pain and also provided the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation.

This would make these drugs, particularly eliapixant, of interest for treatment of different types of bladder disorders, for example, OAB and LUTS and painful bladder syndrome/interstitial cystitis (PBS/IC). However, such clinical studies are still to be performed.

3.2. TRP – channel antagonists

Abundant preclinical information on bladder specimens from animals and humans and on in vivo studies in both species suggests that antagonists for several different types of TRP channels, especially TRPV1, TRPA1, TRPV4, and TRPM8, may be useful for treatment of OAB and LUTS, and/or PBS/IC [44–46].

3.2.1. TRPV1 antagonists

3.2.1.1. Rationale

In 2006, Avelino and Cruz [47] summarized the use of desensitization of the receptor by capsaicin and resiniferatoxin in overactive bladder of neurogenic and non-neurogenic origin and painful bladder syndrome/interstitial cystitis (PBS/IC) and they predicted that this principle may become obsolete when nontoxic, potent TRPV1 antagonists will be available. What progress has been made?

TRPV1 is the best-characterized member of the TRPV subfamily (TRPV1–6) and abundant information on its morphology and function in animal models, and to some extent on the clinical translation of its manipulation, is available [48]. In several mammals, including rats, mice, and humans, TRPV1 channels are highly expressed in C-fibers innervating the urinary bladder and urethra [46,49]. These channels have been shown to play an integral role in modulating the excitability of bladder afferents and the generation of hypersensitivity induced by bladder inflammation [50]. The demonstration that selective TRPV1 channel antagonists had promising effects in several animal models of LUT dysfunction, for example, in rats with neurogenic bladder overactivity after spinal cord injury and mice with lipopolysaccharide (a bacterial toxin)-induced cystitis [49], makes them potential drug targets.

Moreover, it has been reported in six-week-old male mice that social stress can lead to the development of OAB by the induction of TRPV1-dependent an afferent nerve activity, suggesting that TRPV1 channels can be an interesting target also for preventing the development of stress-induced OAB in children [51]. In line with these findings Zhang et al. [52] reported that in urothelium of 21 female patients with OAB expression of TRPV1 in the urothelium was higher than in nine healthy controls and that the high TRPV1 expression of the patients was closely correlated to OAB occurrence. This supports the rationale for development of TRPV1 antagonists for treatment of LUT disorders.

3.2.1.2. Emerging drugs

Unfortunately, it rapidly became clear that TRPV1 antagonists cause an increase in body temperature (hyperthermia), both in animal models and in humans [49,53,54], which limits their clinical application. However, Brown et al. [55] conducted a phase I study in healthy volunteers on the safety and pharmacokinetics of oral NEO6860, a selective TRPV1 antagonist, and found no clinically significant increase in temperature or heat pain threshold/tolerance, but a significant antagonistic effect on intra-dermal capsaicin-induced pain.

The efforts to develop small molecules targeting TRPV1 have produced multiple potent and selective inhibitors (e.g. SB-705498; AMG-517; AZD1386; PHE3779) [see 54], but none of these compounds came close to market authorization. Several reasons contributed to this but the most important is the finding of that acute pharmacological inhibition of TRPV1 evokes hyperthermia, independent of the chemical structure of the antagonist [54]. Thus, there still seems to be no drug candidate on the horizon that can be developed to a clinically useful treatment for LUT disorders, but since the rationale is good further research seems motivated.

3.2.2. TRPA1 antagonists

3.2.2.1. Rationale

TRPA1 channels are expressed in C-fiber endings in the suburothelium where they are co-localized with CGRP. They are considered to be mediators of inflammation and pain, but they have been suggested to play a role not only in pain signaling but also in mechanosensory transduction in the bladder and urethra [56,57], since agonists can cause bladder overactivity. TRPA1 channels may be potential targets in the treatment of, for example, visceral hypersensitivity syndromes such as inflammatory bowel disease, and in OAB, LUTS, and PBS/IC.

3.2.2.2. Emerging drugs

In rats with bladder overactivity after spinal cord injury, the TRPA1 antagonist, HC030031, improved cystometric parameters. In these animals, where TRPA1 expression in dorsal root ganglia (DRG) was upregulated at the protein and mRNA levels, the effects of HC030031 could be mimicked by TRPA1 RNA knockdown [58]. Using cyclophosphamide-induced cystitis as a visceral pain model, DeBerry et al. showed that HC030031 effectively alleviated cystitis-induced bladder hyperalgesia [59]. Despite promising animal experiments, clinical development of HC030031 was not continued [54].

GRC-17536 was one of the first TRPA1 antagonists to initiate phase I development. The drug was well tolerated and demonstrated a reasonable pharmacokinetic profile. GRC-17536 still seems to be a candidate for full clinical development [54]. Several other TRPA1 antagonists have been tried in humans, but even if the therapeutic potential of the ion channel was supported by promising clinical results, poor pharmaceutical and pharmacokinetic properties hampered further development [54].

Available data suggest that TRPA1 does not have a substantial role in normal bladder

function, but is a detector of noxious stimuli that can contribute to bladder pain perception and nociceptive behavior [46]. Although TRPA1 antagonists show efficacy in various animal models for bladder pain and hyperalgesia [60,61], they await clinical validation in LUT disorders.

3.2.3. TRPV4 antagonists

3.2.3.1. Rationale

In mice, rats, Guinea pigs, and humans, functional TRPV4 channels were found to be expressed in the urothelium, predominantly on the surface of the basal urothelial cells [46,49,62,63]. Compared to controls, cultured urothelial cells from TRPV4 KO mice showed an attenuated Ca2+-influx and ATP release in response to stretch [64]. A reduced stretch-evoked ATP release was also demonstrated in isolated TRPV4 KO mouse bladders. In vivo, TRPV4 KO mice exhibited less frequent voiding [62] and larger bladder capacity than controls [65].

When infused intravesically the potent TRPV4 agonist, GSK1016790A, induced bladder hyperactivity in rodents [65,66]. The drug also increased afferent firing of capsaicin-insensitive C-fibers [66]. Another TRPV4 antagonist, HC067047, increased bladder capacity, and reduced micturition frequency when given systemically in a mouse model of cyclophosphamide-induced cystitis [67]. Taken together, these findings suggest that TRPV4 channels act as mechano-sensors in urothelial cells, activating the underlying C-fiber afferent nerves via ATP-release. In a rodent model of cystitis, co-administration of antagonists to both TRPV4 and TRPV1 potentiated the effect of each drug in reducing bladder hyperactivity, suggesting advantages of combined therapy [68].

3.2.3.2. Emerging drugs

Interestingly, in rodents no significant adverse effects of systemic treatment with the TRPV4 antagonists HC067047 and GSK2193874 have been reported [67,69]. Recently, two clinical trials of GSK2798745, a highly potent, selective, orally active TRPV4 antagonist, demonstrated its safety and pharmacokinetics in healthy subjects and patients with heart failure [70]. Although TRPV4 antagonists might eventually precipitate urinary retention [62], GSK2798745 seems to be a promising drug candidate also for OAB and LUTS.

3.2.4. TRPM8 antagonists

3.2.4.1. Rationale

TRPM8 is a polymodal, Ca2+-permeant, and nonselective cation channel, identified as the physiological sensor of environmental cold. It is activated by cool temperatures (8–25°C) and by chemicals that provoke ‘cool’ sensations, such as menthol and icilin. TRPM8 is widely distributed in the body and predominantly expressed in a subpopulation of sensitive primary afferent neurons [71,72]. In the human bladder, Mukerji et al. [73] demonstrated TRPM8 expression in a subset of small nerve fibers. The channel was also expressed in dorsal root ganglion neurons innervating the rat bladder [74].

Confirming the relation between cold sensing and TRPM8, systemic application of the TRPM8 antagonist, BCTC, reduced cold stress-induced bladder overactivity in rats [75]. Intravenous administration of the TRPM8 channel antagonist, AMTB, inhibited isovolumetric bladder contractions, and bladder nociceptive reflex responses in the rat. This suggested TRPM8 channels may also be involved in the afferent control of micturition and nociception [76]. In line with this, Ito et al. [77] showed in an ex vivo rat model that TRPM8 channels have a role in activation of mechanosensitive C-fiber bladder afferent activity.

Systemic application of TRPM8 antagonists generally decreases deep body temperature (hypothermia) [77,78]. This is a concern that may limit clinical use of TRPM8 antagonists for treatment of OAB and LUTS and hypersensitive bladder disorders

In contrast to classical TRPM8 antagonists, KRP-2579, a novel TRPM8 antagonist, showed a suppressive effect on acetic-acid- induced bladder overactivity and associated hyperactivity of bladder mechanosensitive C-fibers without affecting deep body temperature in the rat [79]. It has been more recently reported that KRP-5714, another novel TRPM8 antagonist, similarly can improve acetic-acid-induced bladder overactivity and the hyperactivity of mechanosensitive C-fibers of bladder afferents in anesthetized rats [80]. In addition, KPR-5714 was shown to improve voiding behavior in conscious rats with cerebral infarction and in those exposed to cold. Combined administration of KPR-5714 and mirabegron or tolterodine tartrate showed additive effects on bladder overactivity in rats with cerebral infarction or rats exposed to cold temperature, respectively [81], suggesting that the combination therapy of TRPM8 antagonist and β₃-adrenoceptor agonist or anticholinergic agent can be a potential treatment option.

3.2.4.2. Emerging drugs

The high number of TRPM8 antagonist families described by different groups in the last 15 years contrast with the few numbers of TRPM8 modulators that have reached clinical trials, except menthol [72]. PF-05105679, a selective TRPM8 antagonist, displayed a significant inhibition of pain in the cold pressor test and had no effect on core body temperature in humans. However, an unexpected adverse event (hot feeling) was reported, predominantly perioral, which in two volunteers was non-tolerable [82]. Even if clinical trials with oral agonists and antagonists of TRPM8 have produced important secondary effects that may preclude their progression into the clinic [72], there seems to be a good rationale for further development.

4. Cannabinoid system

4.1. Rationale

The cannabinoid (CB) receptors, their endogenous ligands and related enzymes for biosynthesis and degradation constitutes the endocannabinoid system [22,83,84]. From the cannabis plant cannabinoids (phytocannabinoids) can be extracted. The main compounds in such extracts are THC, cannabidiol, and cannabinol. Two G-protein-coupled CB receptors have been defined: type 1 (CB1) and type 2 (CB2). The G-protein-coupled receptor 55 (GPR55), has been described as a third CB receptor, but its pharmacology is incompletely known. Endocannabinoids and ‘exocannabinoids,’ such as phyto-cannabinoids and synthetic cannabinoids, interact with these receptors and some associated endogenous fatty acid amides (FAA). Within the endocannabinoid system at least two major arachidonate-derived ligands, anandamide, and 2-arachidonoylglycerol (2-AG), mediate their effects by binding to CB1 and CB2 receptors. Both anandamide and 2-AG act extensively in the central and peripheral nervous system. They affect not only LUT function but may influence pain, mood, feeding behavior, motivation, and inflammation [85–87].

In the nervous system, anandamide and 2-AG are primarily metabolized by the serine hydrolase enzymes, fatty acid amide hydrolase (FAAH), and monoacyl-glycerol lipase (MAGL), respectively [84,88]. Prevention of anandamide and 2-AG degradation with inhibitors of these enzymes can enhance their endogenous action. Anandamide and several exogenous CB receptor agonists are known to also act at other receptors, such as the vanilloid TRPV1 channel. Most cannabinoids have the capacity to pass the blood–brain barrier.

Both CB1 and CB2 receptors are widely expressed in the LUT. They can be found in all layers of the bladder wall including the urothelium and different types of afferent nerves [89,90]. The CB2 expressing afferent nerves in the lamina propria were found to also express TRPV1 and/or CGRP, while the nerves in the detrusor expressed the vesicular ACh transporter, suggesting that they were cholinergic. CB1 immunoreactive fiber density was significantly increased in the suburothelium of bladder specimen from patients with painful bladder syndrome and idiopathic DO (IDO). In patients with IDO, the density correlated with their symptom scores, as compared to control [91].

In the spinal cord, CB receptors are involved in modulation of afferent activity [90]. In the lumbosacral part of the cord and in L5-L6/S1 dorsal root ganglia of rats, CB1 and CB2 receptor mRNA and protein have been demonstrated. High to moderate densities of CB1 receptors have been found in many supraspinal structures including the medial frontal cortex, the periaqueductal gray matter, thalamus, and insula [92], but their functional roles of in the control of micturition are incompletely known

4.2. Cannabinoids and micturition

Effects mediated by cannabinoids have been studied both in isolated tissues and in experimental in vivo models of normal micturition and bladder dysfunction [83,93,94]. Anandamide is known to also activate TRPV1 receptors, potentially via the release of CGRP, which makes it difficult to evaluate its effects [95]. In general, cannabinoid receptor agonists have little effect on bladder contractility, but results are not always consistent.

4.3. Fatty Acid Amide Hydrolase (FAAH)

The key enzyme for the degradation of anandamide and other endogenous cannabinoids, is FAAH. FAAH is expressed in the mucosa of mouse, rat and human bladder and co-expressed with CB2 receptors [83,96]. FAAH inhibitors have been explored as potential treatments in several models of bladder dysfunction. In healthy rats, intravenous or intravesical administration of the FAAH inhibitor oleoyl ethyl amide increased inter-contraction intervals, micturition volume, bladder capacity, and threshold pressure while the CB2 receptor antagonist SR 144,528 abolished all effects of oleoyl ethyl amide. The CB1 receptor antagonist, rimonabant, attenuated only those on threshold pressure [96].

URB 937, a peripherally restricted FAAH inhibitor reduced prostaglandin E₂-induced detrusor overactivity and activation of mechanosensitive afferent nerves [97]. In rats with bladder outlet obstruction, oleoyl ethyl amide also reduced detrusor overactivity, and similar findings were obtained the rimonabant or SR 144,528 [98].

4.4. Clinical applications

The FAAH inhibitor, ASP3652, was studied as a treatment of adult male patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). A total of 229 patients were randomized to various doses of ASP3652 or placebo for 12 weeks. ASP3652 was generally safe and well tolerated, but it did not show efficacy on pain symptoms. However, the results indicated that FAAH inhibition may attenuate LUTS, but this has to be confirmed in dedicated studies in LUTS patients [99].

Approved cannabinoid products include dronabinol ((-)-trans-Δ9-tetrahydrocannabinol; THC), nabilone (a THC analogue), and cannabidiol (CBD) that differ in their pharmacology and may thus have different adverse effects [100].

In a systematic review, Taylor and Birch [94] evaluated cannabinoids used to treat certain benign urological pathologies and tried to clarify the clinical value of this data. They concluded that cannabinoids have a therapeutic potential in the management of specific benign urological diseases, most notably neurogenic bladder dysfunction (clinical studies), renal disease (animal studies), and interstitial cystitis (animal studies). They also concluded that whilst cannabinoids are increasingly used, they cannot be considered reliable alternatives to more recognized treatments

Cannabinoids has been tested mainly in patients with multiple sclerosis (MS). In an open-label pilot study Brady et al. [101] reported that MS patients could have a positive effect on LUTS. A few other open label and placebo-controlled studies showed that oral treatment with cannabinoid modulators may reduce NDO. A significant decrease in urinary urgency, the number and volume of incontinence episodes, frequency, and nocturia has been demonstrated after administration of whole plant cannabis extracts containing delta-9-tetrahydrocannabinol and/or cannabidiol to patients with advanced MS and severe LUTS [102–104]. In the CAMS trial [103], 630 patients received 4–10 capsules (depending on body weight) of either placebo, a cannabis extract containing 1.25 mg of cannabidiol (CBD), or 2.5 mg Δ⁹-tetrahydrocannabinol (THC) for 13 weeks. Based on 3-day voiding diaries, placebo, extract and THC reduced number of incontinence episodes by 18%, 38%, and 33%, indicating a 25% and 19% reduction relative to placebo (p = 0.039). Among secondary outcome parameters, pad tests were also improved by the extract and THC relative to placebo, whereas urodynamic tests and the King’s Health questionnaire were not. The symptomatic improvement was not well reflected urodynamically. Side effects with cannabinoids, such as dizziness, light-headedness, attention deficit, fatigue, and disorientation have been reported and are an obvious disadvantage with exocannabinoid therapy.

A meta-analysis of two randomized [103,104] and one open-label trial [101] reported a difference in 0.35 incontinence episodes between active treatment and placebo [105]. A broader meta-analysis of nine randomized studies using various cannabinoids and endpoints found an improvement of bladder function by 0.29 standard deviations for cannabis extracts [CI 0.09; 0.50] and 0.11 standard deviations for cannabinoids [CI 0.0008; 0.20] [106]. Taken together these studies suggest a moderate efficacy of cannabis extracts and cannabinoids in bladder dysfunction associated with multiple sclerosis, but the findings were not sufficiently robust to be detected in all individual studies.

Nabata et al. [107] performed a systematic review to examine usage patterns and reasons for cannabinoid use, and to determine the treatment efficacy and safety of cannabinoid use in people with spinal cord injury (SCI). 7,232 studies were screened, and 34 were included in the review. The authors concluded that based on current evidence cannabinoids may reduce pain and spasticity in people with SCI, but its effect magnitude and clinical significance are unclear.

5. MaxiK-channel – gene therapy

One type of large conductance, voltage, and calcium activated K+ channel, known as big potassium (BK) or Maxi-K channel is expressed highly on urinary bladder smooth muscle cells and regulates bladder function [108]. Modulation of this channel with gene therapy has recently been explored and reviewed [109]. URO-902 is a 6880-base-pair naked plasmid DNA incorporating a DNA sequence synthesized from mRNA that encodes the human BK channel alpha subunit [109]. In phase 1 studies women with OAB, gene therapy was administered either by direct bladder injection or bladder instillation [110]. No participants withdrew due to AEs (n = 34) and no AEs prevented dose escalation. Most AEs were mild and not likely related to the therapy. In the instillation study, there was a trend toward a reduction in involuntary detrusor contractions on urodynamics and mean urinary incontinence episodes vs placebo. Furthermore, in those with direct injected gene therapy into the bladder significant reductions vs placebo was seen in urgency episodes (p = 0.036) and number of voids 1 week post injection (p = 0.044).

6. sGC stimulators and activators

The role of nitric oxide (NO) as a relaxing factor in bladder, bladder neck, urethra, and prostate smooth muscle is well established. The target for NO is its intracellular receptor, soluble guanylate cyclase (sGC), which on stimulation produces cyclic GMP (cGMP). The relaxing effect of cGMP is terminated by cGMP-specific 3ʹ,5ʹ-cyclic phosphodiesterase (PDE5), and to some extent, by PDE6 and PDE9A. The clinical efficacy of PDE5 inhibitors (PDE5Is) to ameliorate LUTS associated with BPH is well established. PDE5Is reduce inflammation, tissue proliferation, and nerve-mediated activity in the LUT by increasing oxygenation, while concurrently reducing symptoms [111].

NO binds to the heme group on the β-subunit of sGC, activating its catalytic domain to convert GTP to cGMP. This in turn activates protein kinase G (PKG), phosphorylating multiple downstream proteins. Therapeutically, direct delivery of NO donor drugs has disadvantages, for example, vasodilatation and development of tolerance during long-term administration, and therefore attempts were made to find drugs that act directly on sGC in an NO-independent manner. YC-1 was the first NO-independent and heme-dependent sGC stimulator but owing to the poor adverse effect profile of YC-1, novel compounds with increased potency and selectivity were developed [112–114], primarily for treatment of cardiovascular diseases: NO-independent, heme-dependent stimulators of sGC (BAY 41–2272, BAY 41–8523, BAY 63–2521, and BAY 60–4552) and NO-independent, heme-independent sGC activators (HMR 1766, BAY 58–2667, and BAY 60–2770). These drugs may be effective for patients who are refractory to PDE5Is.

One of the sGC activators, cinaciguat (BAY 58–2667), was recently studied by Zabbarova et al. [115] who demonstrated that in aged mice/rats, exhibiting histologic, morphologic, and urodynamic features of human BPH/LUTS, the drug ameliorated these symptoms only transient (1 h) cardiovascular effects with oral gavage, suggesting a positive safety profile. Cinaciguat also improved bladder function in cyclophosphamide-induced cystitis in mice [116]. Cinaciguat has been tested in healthy volunteers [117] and in patients with acute decompensated heart failure and was well tolerated [118]. These findings make this drug an interesting candidate for further testing in patients with LUT dysfunction.

7. Conclusions

Lower urinary tract disorders have multiple pathophysiologies. This is a challenge but also offers many targets for treatment drugs. Existing therapies (with the exception of long-term treatment with antimuscarinics) are generally well tolerated but also have low efficacy and new agents with new mechanisms of action are desirable. Unfortunately progress in the field of new drug development has been slow and few new drug candidates have emerged that can be expected to be introduced clinically within the immediate future. However, there are developments that provide cause for an optimistic perspective toward future treatment of disorders, such as OAB, LUTS, and PCS/IC.

8. Expert opinion

Many emerging drugs/drug principles have shown promise for treatment of LUT disorders in preclinical and early clinical studies. When assessing the potential of these drugs to reach the clinic, several considerations have to be made. Are the drugs of ‘me too’ type, i.e. do they belong to already approved principles or are they new, previously untested approaches? It should be remembered that the approved drugs have proven efficacy and acceptable AEs, and to prove that e.g. selective b₃-receptor agonists in pipeline, such as solabegron and ritobegron, are as effective or more effective than mirabegron and vibegron, or that they are better tolerated, would require extensive clinical trial programs, which would be economically questionable. Likewise, new antimuscarinics such as tarafenacin, afacifenacin, and DA-8010 may have interesting in vitro profiles, but to translate these into clinical advantages over existing antimuscarinic drugs should be difficult and costly. Concerns about long-term effects on cognitive functions by antimuscarinics have been discussed extensively, and particularly in the treatment of neurogenic LUTS, where often high doses are prescribed, it would be relevant to use other alternatives (e.g. b3-adrenoceptor agonists) or combination therapy to decrease the ‘anticholinergic burden.’ Drugs like litoxetine may be well tolerated: treatment-emergent adverse events equaled those of placebo, and even if it was concluded that the drug may be a safe, effective and well‐tolerated treatment, efficacy data were not convincing, and a place for the drug in incontinence treatment awaits further documentation. Several drugs, for example, NK1-receptor antagonists, the tachykinin release inhibitor, cizolirtine, and the vitamin D₃ analogue, elocalcitol, have not fulfilled expectations. Even if the drugs represent unique principles, they have not shown convincing efficacy compared to existing alternatives and further development seems questionable. Gene therapy with injected Maxi-K channels is an interesting development, but requires intravesical administration, which may offer problems. The renewed interest in sGC stimulators and activators with focus on the sGC activator, cinaciguat, may result in clinically useful alternatives, but the lack of clinical proof of concept in LUT conditions makes it difficult to assess its possibilities to become a treatment of LUT disorders.

Recently, two selective P2X3 receptor antagonists, gefapixant (AF-219, MK-7264) and eliapixant (BAY 1817080), have been demonstrated to have efficacy in patients with refractory chronic cough with good tolerance, except that gefapixant caused taste disturbances. Since gefapixant also showed a significant reduction in urinary urgency and a positive trend in the improvement of pain in patients with IC/BPS, there is a possibility that this drug (and eliapixant) can be an alternative also for OAB and LUTS patients. Further studies, particularly with eliapixant, which seems to have minimal effects on taste perception are desirable, considering the good preclinical rationale for P2X3 receptor antagonism as a therapeutic approach.

Other potential drug targets that would be worthwhile to further explore clinically are the different TRP channels. It has been known for decades that TRPV1 receptors are involved in afferent signaling in humans as shown by the agonists, capsaicin, resiniferatoxin. In sufficient dosage these drugs are clinically effective in bladder overactivity and then act by inactivating the receptors by desensitization. However, even if they prove the principle of inactivation of the receptors, they are associated with many disadvantages, making blockade of the receptor a more attractive approach. However, the development of small molecule blockers of different TRP channels has been slow and disappointing and most compounds still need to be tested on urological disorders. Blockers of TRPV1 channels have so far not been successful due to hypothermia and the only agent showing promise is the TRPA1 blocker, GRC-17356.

To develop drugs for treatment of LUTS disorders that act on the complicated cannabinoid system is to face many challenges. However, this approach may also offer interesting possibilities. It may be speculated that a drug, or more likely a combination of agents, acting at CB receptors both peripherally and centrally could increase efficacy to new levels. So far, a clinical effect of cannabis only has been demonstrated on incontinence episodes in patients with multiple sclerosis, and the role of agents acting directly on CB1 and CB2 receptor or indirectly via endocannabinoids by inhibition of FAAH has to be established. They may show promising effects experimentally, but satisfactory clinical trials are still lacking. Information on optimal dosage, method of use, composition and concentration of compounds is lacking, which limits assessment of the treatment potential of different available compounds. Long-term, double-blind, randomized controlled trials, assessing a wide range of outcomes should be conducted to further understand the effects of cannabinoid use in patients with LUT disorders.

New potential alternatives to currently used drugs/drug principles are available, but clinical testing is required before they can be properly evaluated. It therefore seems that for the near future individualized treatment with current drugs and their combinations will be the prevailing therapeutic approach.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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Funding

This paper was not funded.