After the approval and introduction of mirabegron, tadalafil, and botulinum toxin A for treatment of lower urinary tract symptoms/overactive bladder, focus of interest has been on their place in therapy versus the previous gold standard, antimuscarinics. However, since these agents also have limitations there has been increasing interest in what is coming next - what is in the pipeline? Despite progress in our knowledge of different factors involved in both peripheral and central modulation of lower urinary tract dysfunction, there are few innovations in the pipe-line. Most developments concern modifications of existing principles (antimuscarinics, beta3-receptor agonists, botulinum toxin A). However, there are several new and old targets/drugs of potential interest for further development, such as the purinergic and cannabinoid systems and the different members of the transient receptor potential channel family. However, even if there seems to be good rationale for further development of these principles, further exploration of their involvement in lower urinary tract function/dysfunction is necessary.
Adrenergic beta-3 Receptor Agonists/therapeutic use ; Botulinum Toxins, Type A/therapeutic use ; Drug Therapy, Combination ; Humans ; Molecular Targeted Therapy/methods/trends ; Muscarinic Antagonists/therapeutic use ; Neuromuscular Agents/therapeutic use ; Urinary Bladder, Overactive/*drug therapy

The symptoms of interstitial cystitis (IC)/bladder pain syndrome (BPS) may have multiple causes and involve many contributing factors. Traditional treatments (intravesical instillations) have had a primary focus on the bladder as origin of symptoms without adequately considering the potential influence of other local (pelvic) or systemic factors. Systemic pharmacological treatments have had modest success. A contributing factor to the low efficacy is the lack of phenotyping the patients. Individualized treatment based on is desirable, but further phenotype categorization is needed. There seems to be general agreement that IC is a unique disease and that BPS is a syndrome with multiple pathophysiologies, but this has so far not been not been well reflected in preclinical research with the aim of finding new pharmacological treatments. Current research approaches, including anti-nerve growth factor treatment, anti-tumor necrosis factor-α treatment, activation of SHIP1 (AQX-1125), and P2X3 receptor antagonists, and α1-adrenoceptor antagonists are potential systemic treatments, implying that not only the bladder is exposed to the administered drug, which may be beneficial if the IC/BPS is a bladder manifestation of a systemic disease, or negative (adverse effects) if it is a local bladder condition. Local treatment approaches such as the antagonism of Toll-like receptors (which still is only experimental) and intravesical liposomes (with positive proof-of-concept), may have the advantages of a low number of systemic adverse effects, but cannot be expected to have effects on symptoms generated outside the bladder. Assessment of which of the treatment approaches discussed in this review that can be developed into useful therapies requires further studies.
Cystitis, Interstitial ; Humans ; Liposomes ; Necrosis ; Nerve Growth Factor ; Phenotype ; Receptors, Purinergic P2X3 ; Toll-Like Receptors ; Tumor Necrosis Factor-alpha ; Urinary Bladder*

The clinical success of mirabegron as the first β₃-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of β₃-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β₃-AR stimulation have still not been established. The recent demonstration of β₃-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that β₃-ARs can be found these structures. However, recent studies suggest that the β₃-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β₃-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.
Acetylcholine ; Lower Urinary Tract Symptoms ; Muscle, Smooth ; Neurons ; Relaxation ; Urethra ; Urinary Bladder* ; Urinary Bladder, Overactive ; Urothelium

Chronic pelvic pain (CPP) is a common condition involving multiple, organ-specific medical specialties, each with its own approach to diagnosis and treatment. Management requires knowledge of the interplay between pelvic organ function and neuro-functional anatomy, and of the neurologic and psychological aspects of CPP, but no current specialty fully encompasses this approach. Neuropelveology is an emerging discipline focusing on pathologies of the pelvic nervous system on a cross-disciplinary basis. It involves a neurological/neurosurgical approach, combining the knowledge required for a proper neurologic diagnosis, confirmation by transvaginal/transrectal examination of the pelvic nerves, and advanced laparoscopic surgery in selected cases of CPP. The management of CPP requires multidisciplinary contributions, and neuropelveology may offer an educational framework for the interdisciplinary exchange of knowledge between clinical physicians and basic researchers.
Diagnosis ; Laparoscopy ; Nervous System ; Pathology ; Pelvic Pain*