Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders

Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle

“…We assessed contractions by α 1 -adrenergic agonists in prostate and arteries, and of carbachol in detrusor tissues, as the corresponding receptors are principal mediators of smooth muscle contraction in these organs and/or important targets for medical treatment (Gravas et al 2023 ; Hennenberg et al 2008 ; Touyz et al 2018 ). α 1 -Adrenoceptor antagonists, muscarinic antagonists, and a panel of antihypertensive drugs are believed to improve LUTS in BPH or OAB or to reduce blood pressure by inhibition of smooth muscle contraction in the prostate, bladder, or cardiovascular system (Michel et al 2023 ; Brouwers et al 2021 ). However, benefits from these drugs are overall insufficient, resulting in high numbers of surgery for BPH, high burden to patients and socioeconomic costs of LUTS, and high numbers of deaths due to cardiovascular diseases (Zhou et al 2021 ; Michel et al 2023 ; Hennenberg et al 2014 ; Magistro and Stief 2020 ).…”

“…Worldwide, numbers of LUTS patients have been extrapolated up to 2.2 billion for 2018, while annual deaths have been recently estimated up to 10.4 million for elevated systolic blood pressure and to 18.8 million for any cardiovascular disease (Irwin et al 2011 ; Roth et al 2020 ; Zhou et al 2021 ). First-line options for medical LUTS treatment include α 1 -adrenoceptor antagonists for voiding symptoms attributed to benign prostatic hyperplasia (BPH) and muscarinic receptor antagonists for storage symptoms in overactive bladder (OAB), believed to improve symptoms by inhibition of α 1 -adrenergic smooth muscle contraction in the prostate or of cholinergic contractions in the bladder (Gravas et al 2023 ; Michel et al 2023 ). Gold standard options for treatment of cardiovascular diseases are based on drugs inducing vasorelaxation (Brouwers et al 2021 ), whereas hypotensive side effects may limit medical LUTS treatment, in parallel to insufficient symptom improvements (Gravas et al 2023 ).…”

Effect of bladder outlet procedures on urodynamic assessments in men with an acontractile or underactive detrusor: A systematic review and meta‐analysis

“…The ICS definition of DU remains the only generally accepted definition, but it does not provide quantitative guidance. 36 It does not specify existing nomograms or cut-off values, despite attempts by various researchers to identify such values for the BCI and BOO. [38][39][40] A suggestion is to use the Watts factor because it represents detrusor contraction power based on detrusor pressure, contraction speed, and bladder volume.…”

“…While reduced sympathetic inhibition may facilitate spontaneous voiding, pharmacological treatment with alpha-blockers has not been recommended in guidelines due to the absence of adequately powered, placebocontrolled, randomized, double-blind trials. 36 Therefore, it is more reasonable to assume that the restoration of voiding is more dependent on anatomical changes following a bladder outlet procedure rather than on sympathetic nerve destruction alone.…”

Efficacy of KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, on chronic psychological stress‐induced bladder overactivity in male rats

“…TRPM8 is expressed predominantly in a subset of small nerve fibers in the human bladder 1 and dorsal root ganglion neurons innervating the rat bladder 2 . This channel is primarily involved in the abnormal sensation in the bladder and represents an attractive target in the lower urinary tract 3,4 . Recently, several TRPM8 antagonists have been reported, and inhibition of TRPM8 may be promising for the treatment of overactive bladder and hypersensitive bladder disorders 5–7 …”