Drugs Currently Undergoing Preclinical or Clinical Trials for the Treatment of Overactive Bladder: A Review

Joseph, Silvia; Maria, Steffi A.; Peedicayil, Jacob

doi:10.1016/j.curtheres.2022.100669

Cited by 22 publications

(24 citation statements)

References 71 publications

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“…There has been a longstanding interest in investigating the role of Rho kinase, a Ca 2+ -independent mechanism, in receptor-mediated contractions ( 20 , 56 ), with this pathway hypothesized to present a potentially novel target in the future treatments of bladder contractile disorders ( 57 ). In previous experiments, inhibition of extracellular Ca 2+ influx reduced contractions, but not to a level where it was sufficient to entirely abolish the G q/11 -mediated U&LP responses ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

The role of intracellular calcium and Rho kinase pathways in G protein-coupled receptor-mediated contractions of urinary bladder urothelium and lamina propria

Phelps

Chess-Williams

Moro

2023

American Journal of Physiology-Cell Physiology

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The influence of extracellular and intracellular calcium (Ca2+) on smooth muscle contractile activity varies between organs. In response to G protein-coupled receptor (GPCR) stimulation, the urinary bladder detrusor muscle has shown a 70% dependence on extracellular Ca2+, while the urothelium and lamina propria (U&LP) has a 20-50% dependence. However, as this only accounts for partial contractile activity, the contribution of intracellular Ca2+ and Ca2+ sensitization pathways remains unclear. This study assessed the role of intracellular signaling pathways on GPCR-mediated urinary bladder U&LP contraction. Porcine U&LP responses to activation of the muscarinic, histaminergic, 5-hydroxytryptamine (serotonin), neurokinin, prostaglandin, and angiotensin II receptors were assessed with three selective inhibitors of store-released intracellular Ca2+, 2-APB, CPA, and ruthenium red, and three Rho kinase inhibitors, fasudil, Y-27632, and GSK269962. There was no discernible impact on receptor agonist-induced contractions of the U&LP after blocking intracellular Ca2+ pathways, suggesting this tissue is more sensitive to alterations in the availability of extracellular Ca2+. However, an alternative mechanism of action for GPCR-mediated contraction was identified to be the activation of Rho kinase. For example, Y-27632 significantly reduced the GPCR-mediated contractile activity of the U&LP by about 50% (p>0.05, n=8 for all). This suggests that contractile responses of the bladder U&LP do not involve a significant release of Ca2+ from intracellular stores, but that receptor activation causes Ca2+ sensitization via Rho kinase. This study presents a key role for Rho kinase in the urinary bladder, which may provide a novel target for the future pharmaceutical management of bladder contractile disorders.

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Section: Discussionmentioning

confidence: 99%

The role of intracellular calcium and Rho kinase pathways in G protein-coupled receptor-mediated contractions of urinary bladder urothelium and lamina propria

Phelps

Chess-Williams

Moro

2023

American Journal of Physiology-Cell Physiology

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“…110,111 In the near future, medicines such as the anticholinergics (tarafenicin and afacifenacin), β3-adrenergic receptor blockers (solabegron, ritobegron) drugs that open potassium and calcium channels, phosphodiesterase (PDE)-5 inhibitors, Rho kinase inhibitors as well as pregabalin and trimetazidine may be approved for the therapy of the neurogenic bladder. 112 Surgically, sacral neuromodulation through an implant, which stimulates the sacral nerve may have a positive effect on bladder symptoms in addition to a positive effect on faecal incontinence and even sexual function. 113…”

Section: Colonic Dysfunctionmentioning

confidence: 99%

Detecting and treating the protean manifestations of diabetic autonomic neuropathy

Bell¹

2023

Diabetes Obesity Metabolism

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The manifestations of diabetic autonomic neuropathy (DAN) are protean and clinically involve multiple systems, including the cardiovascular system, the gastrointestinal system, the genitourinary system as well as the sweat glands (sudomotor dysfunction) and the gallbladder. In addition, cardiac autonomic neuropathy (CAN) is associated with a correctible inability to appreciate and correct hypoglycaemia. While not a clinical problem, pupillary involvement should be the clue and the catalyst to investigate for other manifestations of DAN. This review outlines a practical approach to detecting and investigating the manifestations of DAN. Of particular importance is early detection of cardiovascular involvement where prompt therapy through glycaemic control can decrease the severity of CAN and decelerate the frequency and severity of retinopathy and nephropathy in addition to decreasing cardiovascular events and mortality. CAN also plays a role in accelerating other diabetic complications such as acute ischaemic stroke, heart failure, medial artery calcinosis, foot ulcers, peripheral artery disease and Charcot joints. Many therapies of DAN are available, which should not only decrease morbidity and mortality from DAN, but also improve the patient's quality of life. However, the therapies available are largely symptomatic.

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“…The beta‐3‐adrenoceptor agonist mirabegron, which is better tolerated than anticholinergic drugs with a comparable overall efficacy, acts to induce detrusor relaxation 11 but may affect the cardiovascular system and has pharmacokinetic interactions with other drugs 31,32 . Antimuscarinics and beta‐3‐adrenoreceptor agonizts are the most commonly administered treatments for overactive bladder and UUI; these can be administered as combination therapies to increase efficacy and tolerability, and other pharmacologic options with alternative action mechanisms also exist 24,33,34 …”

Section: Standard Treatmentsmentioning

confidence: 99%

“…Various other pharmacologic treatments targeting other mechanisms of action are in development for overactive bladder and UUI, but these have, for the most part, not proceeded to clinical stages of development yet 33 . Some that have reached clinical phases of development include phosphodiesterase‐5 inhibitors, such as tadalafil, and purinergic P2X 3 receptor agonizts, such as eliapixant 34 .…”

Section: Emerging Treatmentsmentioning

confidence: 99%

“…31,32 Antimuscarinics and beta-3-adrenoreceptor agonizts are the most commonly administered treatments for overactive bladder and UUI; these can be administered as combination therapies to increase efficacy and tolerability, and other pharmacologic options with alternative action mechanisms also exist. 24,33,34 Duloxetine, a serotonin and noradrenaline reuptake inhibitor that increases striated urethral sphincter activity, 35 is approved for the treatment of SUI in Europe; it is currently the only pharmacological option for SUI, although the reported side effects of nausea and suicidality likely prevented its approval in the US. [36][37][38] Surgical procedures are often standard treatment options for SUI in both men and women, but the specific surgical options vary between the genders.…”

Section: Standard Treatmentsmentioning

confidence: 99%

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Mixed urinary incontinence: Are there effective treatments?

Gamé

Dmochowski

Robinson

2022

Neurourology and Urodynamics

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The aim of this debate article is to discuss whether effective treatments are available for mixed urinary incontinence (MUI). Because patients with MUI have both stress and urgency urinary incontinence (SUI and UUI) episodes and current treatment guidelines currently recommend treating the predominant symptom first, this article presents standard and emerging treatments for both SUI and UUI before discussing how well these treatments meet the medical needs of patients with MUI. Standard treatments presented include noninvasive options such as lifestyle changes and pelvic floor exercises, pharmacological agents, and surgery. Treatment of all three types of urinary incontinence (UI) is usually initiated with noninvasive options, after which treatment options diverge based on UI subtype. Multiple pharmacological agents have been developed for the treatment of UUI and overactive bladder, whereas surgery remains the standard option for SUI and stress-predominant MUI. The divide between UUI and SUI options seems to be propagated in emerging treatments, with most novel pharmacological agents still targeting UUI and even having SUI and stress-predominant MUI as exclusion criteria for participation in clinical trials. Considering that current treatment options focus almost exclusively on treating the predominant symptom of MUI and that emerging pharmacological treatments exclude patients with stresspredominant MUI during the development phase, effective treatments for MUI are lacking both in standard and emerging practice. Ideally, agents with dual mechanisms of action could provide symptom benefit for both the stress and urgency components of MUI.

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Drugs Currently Undergoing Preclinical or Clinical Trials for the Treatment of Overactive Bladder: A Review

Cited by 22 publications

References 71 publications

The role of intracellular calcium and Rho kinase pathways in G protein-coupled receptor-mediated contractions of urinary bladder urothelium and lamina propria

The role of intracellular calcium and Rho kinase pathways in G protein-coupled receptor-mediated contractions of urinary bladder urothelium and lamina propria

Detecting and treating the protean manifestations of diabetic autonomic neuropathy

Mixed urinary incontinence: Are there effective treatments?

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