BoNT/A in the Urinary Bladder—More to the Story than Silencing of Cholinergic Nerves

Ibrahim, Hodan; Maignel, Jacquie; Hornby, Fraser; Daly, Donna; Beard, Matthew

doi:10.3390/toxins14010053

Cited by 6 publications

(2 citation statements)

References 144 publications

(214 reference statements)

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“…Depletion of NLPR3 gene prevented the unfavorable effect of diabetes on bladder (Hughes et al 2019 ). Botulinum toxin A was approved by FDA and NICE in OAB patients who do not respond or tolerate anticholinergic drugs (Ibrahim et al 2022 ). Intravesical injection of botulinum toxin A inhibits both hypersensivity of detrusor muscle and chronic inflammation.…”

Section: Emerging Pathophysiology-based Treatments Of Lutd In Diabetesmentioning

confidence: 99%

Established and emerging treatments for diabetes-associated lower urinary tract dysfunction

Erdogan

Liu

Arioglu‐Inan

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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Dysfunction of the lower urinary tract (LUT) including urinary bladder and urethra (and prostate in men) is one of the most frequent complications of diabetes and can manifest as overactive bladder, underactive bladder, urinary incontinence, and as aggravated symptoms of benign prostate hyperplasia. We have performed a selective literature search to review existing evidence on efficacy of classic medications for the treatment of LUT dysfunction in diabetic patients and animals, i.e., α1-adrenoceptor and muscarinic receptor antagonists, β3-adrenoceptor agonists, and phosphodiesterase type 5 inhibitors. Generally, these agents appear to have comparable efficacy in patients and/or animals with and without diabetes. We also review effects of antidiabetic medications on LUT function. Such studies have largely been performed in animal models. In the streptozotocin-induced models of type 1 diabetes, insulin can prevent and reverse alterations of morphology, function, and gene expression patterns in bladder and prostate. Typical medications for the treatment of type 2 diabetes have been studied less often, and the reported findings are not yet sufficient to derive robust conclusions. Thereafter, we review animal studies with emerging medications perhaps targeting diabetes-associated LUT dysfunction. Data with myoinositol, daidzein, and with compounds that target oxidative stress, inflammation, Rac1, nerve growth factor, angiotensin II receptor, serotonin receptor, adenosine receptor, and soluble guanylyl cyclase are not conclusive yet, but some hold promise as potential treatments. Finally, we review nonpharmacological interventions in diabetic bladder dysfunction. These approaches are relatively new and give promising results in preclinical studies. In conclusion, the insulin data in rodent models of type 1 diabetes suggest that diabetes-associated LUT function can be mostly or partially reversed. However, we propose that considerable additional experimental and clinical studies are needed to target diabetes itself or pathophysiological changes induced by chronic hyperglycemia for the treatment of diabetic uropathy.

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Section: Emerging Pathophysiology-based Treatments Of Lutd In Diabetesmentioning

confidence: 99%

Established and emerging treatments for diabetes-associated lower urinary tract dysfunction

Erdogan

Liu

Arioglu‐Inan

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Recent studies have demonstrated that BTX-A injections can diminish bladder sensory nerve function by reducing the expression of various receptors on afferent nerve fibers, such as ATP receptors P2X3 and transient receptor potential vanilloid subfamily-1 (TRPV1) ( Chuang et al, 2010 ). Additionally, intravesical BTX-A injections in rodent bladders have been shown to reduce SNAP-23 levels and inhibit ATP and neurotrophin release from the urothelium while increasing nitric oxide levels ( Ibrahim et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Ultrasound-assisted intravesical botulinum toxin A delivery attenuates acetic acid—induced bladder hyperactivity in rats

et al. 2023

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Background: Intradetrusor injection of botulinum toxin A (BTX-A) is an effective treatment for overactive bladder (OAB). However, the occurrence of adverse events associated with BTX-A injection therapy hinders its acceptance among patients and its clinical promotion. Intravesical instillation of BTX-A offers a promising alternative to injection therapy for treating OAB. Nevertheless, due to the presence of the bladder permeability barrier (BPB) and the high molecular weight of BTX-A, direct instillation is unable to penetrate the bladder urothelium.Purpose: This study aims to investigate the safety and feasibility of ultrasound-assisted intravesical delivery of BTX-A and its potential benefits in a rat model of bladder hyperactivity induced by acetic acid instillation.Methods: Hengli BTX-A and microbubbles (MB) were mixed and prepared as a novel complex. The size distribution and zeta potentials of the complex were measured. On day 1, rats’ bladders were instilled with 1 mL of saline, BTX-A (20 U in 1 mL), MB, or MB-BTX-A (20 U in 1 mL) complex with or without ultrasound (US) exposure (1 MHz, 1.5 W/cm2, 50% duty cycle, sonication for 10 s with a 10-s pause for a total of 10 min). The instillations were maintained for 30 min. After 7 days, cystometry was performed by filling the bladder with saline and 0.3% acetic acid (AA). Bladders were collected, weighed, and processed for immunoblotting, enzyme-linked immunosorbent assay (ELISA), histologic, and immunofluorescence analyses. Expression and distribution of SNAP-25 and SNAP-23 were assessed using Western blot and immunofluorescence. Calcitonin gene-related peptide (CGRP) in the bladder was detected using ELISA.Results: Intercontraction intervals (ICI) decreased by 72.99%, 76.16%, and 73.96% in rats pretreated with saline, BTX-A, and US + MB, respectively. However, rats treated with US + MB + BTX-A showed a significantly reduced response to AA instillation (57.31% decrease in ICI) without affecting amplitude, baseline pressure, or threshold pressure. Rats treated with US + MB + BTX-A exhibited increased cleavage of SNAP-25 and CGRP expression compared to the control group.Conclusion: Ultrasound-assisted intravesical delivery of BTX-A, with the assistance of MB cavitation, led to cleavage of SNAP-25, inhibition of calcitonin gene-related peptide release from afferent nerve terminals, and amelioration of acetic acid-induced bladder hyperactivity. These results support ultrasound-assisted intravesical delivery as an efficient non-injection method for administering BTX-A.

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Botulinum Toxin Therapy for Bladder Pain Syndrome/Interstitial Cystitis

Rahnama’i

Marand

Janssen

et al. 2023

Curr Bladder Dysfunct Rep

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Purpose of Review Bladder pain syndrome (BPS)/interstitial cystitis (IC) can also be classified as either non-ulcerative or ulcerative, corresponding to the characteristic cystoscopic findings under hydrodistention. Promising therapeutic effects, including decreased bladder pain, have been reported from recent clinical trials using botulinum toxin A (BoNTA) for the treatment of BPS/IC. This review summarizes the current state of the literature on the underlying mechanisms of BoNTA therapy in BPS/IC as well as new forms of its application. Recent Findings BoNTA has its effect in the central nervous system in the afferent nerves as well as in the bladder wall. Besides the well-known effects of BoNTA in the nervous system, pain control as well as reduction of urinary urgency in BPS patients could be achieved by mast cell stabilization effecting histamine release as well as modulation of TRPV and PGE2 pathways, among other systems. In addition, new forms of BoNTA administration have focused on intravesical instillation of the drug in order to circumvent bladder wall injections. Hyperthermia, intravesical hydrogel, and lysosomes have been studied as new ways of BoNTA application in BPS/IC patients. From the available studies, bladder instillation of BoNTA in combination with EMDA is the most promising and effective novel approach. Summary The most promising novel application methods for BoNTA in patient with BPS/IC are bladder instillations. Future research needs to point out if bladder instillations with BoNTA with some form of bladder absorption enhancement such as hyperthermia or EMDA would be able to replace BoNTA injections in patients with BPS/IC

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BoNT/A in the Urinary Bladder—More to the Story than Silencing of Cholinergic Nerves

Cited by 6 publications

References 144 publications

Established and emerging treatments for diabetes-associated lower urinary tract dysfunction

Established and emerging treatments for diabetes-associated lower urinary tract dysfunction

Ultrasound-assisted intravesical botulinum toxin A delivery attenuates acetic acid—induced bladder hyperactivity in rats

Botulinum Toxin Therapy for Bladder Pain Syndrome/Interstitial Cystitis

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