New targets for overactive bladder-ICI-RS 2109.

AIM: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. METHODS: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. RESULTS: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide-dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for ß3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1 , TRPV4 , TRPA1 , and TRPM4 ) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+ -activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-ß pathway-the canonical fibrosis pathway. CONCLUSIONS: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.

Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including ß3-Adrenoceptor Agonists -Basic Research Perspectives.

Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. ß3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a ß3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial ß3-AR.

Use of Bladder-Related Medication in Non-Muscle Invasive Bladder Cancer Patients.

Repeated transurethral bladder resections (TURBs) and instillation treatments in non-muscle invasive bladder cancer (NMIBC) might influence bladder function and, therefore, quality of life. Bladder-related medication is a surrogate marker of compromised bladder function. The objective was to investigate whether TURBs and adjuvant instillation therapy are associated with the use of anticholinergics, ß3-agonists, and cystitis-relevant antibiotics. We divided all Danish patients diagnosed with primary NMIBC during 2002-2017 registered in the Danish National Patient Registry (DNPR) based on TURB-load within the first five years from diagnosis (1 TURB, 2-4 TURBs, ≥5 TURBs). Instillation therapy with either mitomycin C (MMC) or bacillus Calmette-Guerin vaccine (BCG) was independent exposure (yes or no). We included 17,774 patients; 76% men, median age: 70 years (IQR: 63, 77). Patients exposed to ≥5 TURBs had a higher risk of using bladder-relaxing medication than patients exposed to 1 TURB, HR = 4.01 [3.33; 4.83], and higher risk of cystitis, HR = 2.27 [2.05; 2.51]. BCG-exposed patients had a higher risk of bladder-relaxing medication use compared to non-exposed, HR = 1.92 [1.69; 2.18], and a higher risk of cystitis, HR = 1.39 [1.31; 1.48]. Repeated TURBs have the highest impact on bladder function. Adjuvant instillation therapy is also associated with the use of bladder-related medication.

Overactive bladder: A review and update.

Overactive bladder syndrome is a chronic, disabling condition with physical, psychological and social consequences that significantly affects the quality of life of millions of patients worldwide. The economic impact of this disorder is crucial. Overactive bladder syndrome is a little-known condition, with different manifestations from patient to patient, which causes a great deal of frustration to the medical staff involved. The patient requires a clear explanation and the full support of the attending physician. It is extremely important to establish a correct diagnosis and an effective individualized treatment. The collaboration and understanding of these patients are extremely important aspects. Improving the quality of life in these patients is the main purpose in managing this condition. There are several treatment modalities that may be used progressively, with favorable albeit inconsistent results. This condition remains extremely challenging for specialists and, unfortunately, always one of maximum interest.