Potential Future Pharmacological Treatment of Bladder Dysfunction

Abstract

In the last decades, a number of new antimuscarinic drugs have been introduced for treatment of the overactive bladder (OAB), defined symptomatically (OAB syndrome) or urodynamically (detrusor overactivity). Recently, three new drug principles have been approved for clinical use, the b 3 -adrenoceptor agonist, mirabegron, the phosphodiesterase-5 inhibitor, tadalafil and the blocker of afferent and efferent nerves, botulinum toxin. However, new alternatives are continuously being explored. OAB is a filling disorder, and ATP is involved in the generation of afferent impulses. One way of blocking the ATP afferent pathway is through the use of P2X3 receptor antagonists. In animal models, this strategy appears to work very well, but whether it translates effectively to man remains to be established. Evidence suggests that components of the endocannabinoid system are involved in regulation of bladder function. Clinical studies of cannabinoid extracts on LUTS are scarce and essentially restricted to patients with MS, and the results have so far not been convincing. Amplification of endocannabinoid activity by inhibiting their degradation via fatty acid amide hydrolase inhibitors may be an attractive approach, but no clinical experiences in OAB have been reported. Studies of the lower urinary tract have indicated that several transient receptor potential (TRP) channels, including TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1, are expressed in the bladder and may act as sensors of stretch and/or chemical irritation. Animal studies have shown that inhibition of these pathways can be effective for the reduction in bladder activity. However, the roles of these channels for normal function and in pathological states have not been established, and so far adverse effects (hyperthermia) have hampered development of antagonists.Lower urinary tract symptoms (LUTS) are generally divided into storage (irritative), voiding (obstructive) and post-micturition components [1]. Particularly, the storage disorder, overactive bladder (OAB), defined symptomatically as the OAB syndrome, or urodynamically as detrusor overactivity (DO), can have major effects on quality of life and social functioning. In addition to antimuscarinic drugs, which still constitute first-line pharmacological treatment of the LUTS/OAB, three new drug principles have recently been approved for clinical use, the b 3 -adrenoceptor agonist, mirabegron, the phosphodiesterase-5 inhibitor tadalafil and the blocker of afferent and efferent nerves, botulinum toxin, whose places in therapy still have to be established [2][3][4][5]. These drugs have good initial response rates, but are not effective in all patients, and alternatives are continuously being explored. There are many agents with theoretically interesting profiles that have been or still are considered as promising, but currently do not seem to be in active development (table 1). For example, nerve growth factor (NGF) and other neurotrophins have been suggested to be an interesting target for treatment and a bioma...

Tadalafil attenuates hypotonicity‐induced Ca2+ influx via TRPV2 and TRPV4 in primary rat bladder urothelial cell cultures

“…This effect might inhibit ATP release and delivery to sensory nerve terminals (Figure ), thereby inhibiting afferent nerve activity. Therefore, tadalafil might improve storage symptoms in BPH‐LUTS and be useful for the treatment of other diseases associated with TRPV2 and TRPV4, such as overactive bladder (Figure ) . The present study has several limitations worth noting.…”

“…TRPV2 has also been shown to function in mouse urothelial cells . Studies of the lower urinary tract have indicated that several TRP channels expressed in the bladder act as sensors of stretch . However, the effects of PDE5‐I tadalafil on the mechanosensory functions of TRP channels in the bladder mucosa remain unknown.…”

Metabolic Syndrome Induced Bladder Cannabinoid Receptor Changes in the Fructose‐Fed Rats

“…Taken together, these findings have demonstrated the potential importance of the cannabinoid receptors in the human bladder physiology and pathophysiology. As a result, these receptors have been viewed as a promising future direction in the pharmacotherapy of LUTS …”

Expressions of urothelial functional proteins in idiopathic detrusor overactivity patients refractory to antimuscarinic therapy with different urodynamic characteristics

“…Recent studies have showed that DO is correlated with dysregulation of neurogenic and purinergic signaling that may lead to sensory‐ or motor‐activated incontinence . In addition, many researches also proposed that increased urinary ATP is the pathogenesis of OAB syndromes.…”