Special Issue "Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions"

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: 30 November 2021.

Special Issue Editors

Prof. Francisco Cruz
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Guest Editor
Faculty of Medicine of Porto, I3S Institute for Investigation and Innovation in Health and Hospital São João
Prof. Dr. Hann-Chorng Kuo
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Guest Editor
Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien Taiwan
Interests: neurourology; urodynamics; female urology; stress urinary incontinence; LUTS
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Special Issue Information

Dear Colleagues,

Seven subtypes of botulinum toxin exist, named A–G, from which only two have been tested in the lower urinary tract and only one, subtype A (BoNT/A), has found its way to clinical application. BoNT/A is available in several different brands with different potencies, which has led the authorities to name them as ona-, abo-, and inco-botulinumtoxinA. To date, only onabotulinumtoxinA has been investigated in NDO and OAB in well-powered trials and licensed for those conditions. However, pivotal trials with the other brands are on their way, and results should be reported soon. Nevertheless, off-label use of abo- and incobotulinumtoxinA in other lower urinary tract conditions is common in urological practice.

The approved form of BoNT/A delivery is through multiple bladder wall injections. The number of punctures and the best place to inject has been the object of several studies, but firm conclusions allowing a reduction of injection points are still lacking. Methods intended to avoid the injection paradigm, in particular the liposomal carrier, seem to have failed. The mechanism of action includes the impairment of cholinergic and sensory nerve terminals and the blockade of the exocrine function of urothelial cells. According to clinical indication, some points of action may be more relevant, linked to the concept of nerve specific botulinum toxins. Direct injection in the central nervous system in lieu of bladder injections, investigated in animal models, has provided stimulating results.

In addition to neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), onabotulinumtoxinA has been investigated for the treatment of lower urinary tract symptoms in men with benign prostate hyperplasia and to relief pain in patients suffering from bladder pain syndrome/interstitial cystitis (BPS/IC). Phase 3 trials, which investigated BoNT/A injection in the prostate, failed to demonstrate a superiority over the placebo. The indication for BPS/IC is under investigation in several centers and, despite the different methods of bladder administration, seems to improve bladder pain. Large phase 3 trials are eagerly awaited.   

After an intense period of research in the beginning of the century, BoNT/A slowly left the spotlight of urological research. However, its common use in urological practice justifies a review of the advances in terms of mechanisms of action, mode of administration, and the situation of BoNT/A in licensed and off-label indications.

Prof. Francisco Cruz
Prof. Dr. Hann-Chorng Kuo
Guest Editors

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Keywords

  • botulinum toxin A
  • onabotA
  • abobotA
  • incobotA
  • NDO
  • OAB
  • BPS
  • IC
  • prostate
  • administration

Published Papers (4 papers)

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Research

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Article
Therapeutic Efficacy of Urethral Sphincteric Botulinum Toxin Injections for Female Sphincter Dysfunctions and a Search for Predictive Factors
Toxins 2021, 13(6), 398; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13060398 - 02 Jun 2021
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Abstract
External urethral sphincter (EUS) dysfunction is a common, bothersome female voiding dysfunction. This study aims to analyze the characteristics of different types of female EUS dysfunction, as well as to determine the outcome predictors of sphincteric botulinum toxin A (BoNT-A) injection. Women receiving [...] Read more.
External urethral sphincter (EUS) dysfunction is a common, bothersome female voiding dysfunction. This study aims to analyze the characteristics of different types of female EUS dysfunction, as well as to determine the outcome predictors of sphincteric botulinum toxin A (BoNT-A) injection. Women receiving sphincteric BoNT-A injections for refractory EUS dysfunction were retrospectively reviewed. A comparison of the baseline clinical, urodynamic parameters and the treatment responses were made for patients with different EUS dysfunctions. A total of 106 females were included. Significantly increased detrusor overactivity, detrusor contracting pressure and the bladder outlet obstruction index with decreased urge sensation were noted in patients diagnosed with dysfunctional voiding or detrusor sphincter dyssynergia comparing to those diagnosed with poor relaxation of the external urethral sphincter. The average subjective improvement rate was 67% for the injection. The therapeutic effect was not affected by the type of EUS dysfunction. The multivariate analysis revealed that bladder neck narrowing and catheterization history were predictive of negative outcomes. There is a distinct urodynamic presentation for each type of female EUS dysfunction. Sphincteric BoNT-A injection provides a good therapeutic outcome for refractory EUS dysfunction. A narrowing bladder neck and a history of catheterization suggest poor therapeutic outcomes. Full article
Article
Therapeutic Effects of Urethral Sphincter Botulinum Toxin A Injection on Dysfunctional Voiding with Different Videourodynamic Characteristics in Non-Neurogenic Women
Toxins 2021, 13(5), 362; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13050362 - 19 May 2021
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Abstract
Although female dysfunctional voiding (DV) is common in urological practice, it is difficult to treat. This study evaluated the therapeutic efficacy of urethral botulinum toxin A (BoNT-A) on non-neurogenic female DV. Based on the videourodynamic study (VUDS), the DV was classified into three [...] Read more.
Although female dysfunctional voiding (DV) is common in urological practice, it is difficult to treat. This study evaluated the therapeutic efficacy of urethral botulinum toxin A (BoNT-A) on non-neurogenic female DV. Based on the videourodynamic study (VUDS), the DV was classified into three subgroups according to the obstructive site. A successful treatment outcome was defined as an improvement of voiding efficiency by 10% and reported global response assessment by ≥1. The study compared therapeutic efficacy, baseline urodynamic parameters, and changes in urodynamic parameters between the treatment success and failure groups and among three DV subgroups. Predictive factors for successful treatment were also investigated. A total of 81 women with DV were categorized into three groups: 55 (67.9%) had mid-urethral DV, 19 (23.5%) had distal urethral DV, and 7 (8.6%) had combined BN dysfunction and mid-urethral DV after BN transurethral incision. The treatment outcome was successful for 55 (67.9%) patients and failed for 26 (32.1%). Successfully treated patients had a significant decrease of detrusor pressure, post-void residual volume, and bladder outlet obstruction index, as well as an increase in voiding efficiency at follow-up versus the treatment failure group. The logistic regression of urodynamic parameters and clinical variables revealed that a greater volume of first sensation of filling predicts a successful BoNT-A treatment outcome (p = 0.047). The urethral BoNT-A injection is effective in treating non-neurogenic women with DV, with a success rate of 67.9%. The videourodynamic characteristics of DV may differ among patients but does not affect the treatment outcome. Full article
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Review

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Review
Botulinum Toxin Injection for Medically Refractory Neurogenic Bladder in Children: A Systematic Review
Toxins 2021, 13(7), 447; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13070447 - 28 Jun 2021
Viewed by 809
Abstract
The objective was to evaluate the use of botulinum toxin A (BTX-A) injection in children with medically refractory neurogenic bladder. A systematic review of the literature was conducted using three databases (Medline via PubMed, Cochrane, and EMBASE). Articles evaluating BTX-A in children with [...] Read more.
The objective was to evaluate the use of botulinum toxin A (BTX-A) injection in children with medically refractory neurogenic bladder. A systematic review of the literature was conducted using three databases (Medline via PubMed, Cochrane, and EMBASE). Articles evaluating BTX-A in children with neurogenic bladder were collected. The clinical and urodynamic parameters were reviewed for the safety and efficacy evaluation. Sixteen studies were selected into this study and a total of 455 children with medical refractory neurogenic bladder were evaluated. All of the patients had received traditional conservative medications such as antimuscarinics and intermittent catheterization as previous treatment. The duration of treatments ranged from 2 months to 5.7 years. Improvements in incontinence and vesicoureteral reflux were the most common clinical outcomes. The detrusor pressure, bladder capacity and bladder compliance improvement were the most common urodynamic parameters which had been reported. However, patient satisfaction with the procedure remained controversial. There was only a minimal risk of minor adverse effects. In all of the studies, BTX-A injection was well tolerated. In conclusion, BTX-A injection appears to be a safe and effective treatment in the management of medically unresponsive neurogenic bladder in children. There is currently no evidence that the use of BTX-A injection could be used as a first-line therapy for neurogenic bladder in children. Full article
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Review
Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders
Toxins 2021, 13(5), 359; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13050359 - 18 May 2021
Viewed by 877
Abstract
Although intravesical botulinum toxin type A (BoNT-A) injection for functional bladder disorders is effective, the injection-related problems—such as bladder pain and urinary tract infection—make the procedure invasive and inconvenient. Several vehicles have recently been developed to deliver BoNT-A without injection, thereby making the [...] Read more.
Although intravesical botulinum toxin type A (BoNT-A) injection for functional bladder disorders is effective, the injection-related problems—such as bladder pain and urinary tract infection—make the procedure invasive and inconvenient. Several vehicles have recently been developed to deliver BoNT-A without injection, thereby making the treatment less or non-invasive. Laboratory evidence revealed that liposome can carry BoNT-A across the uroepithelium and act on sub-urothelial nerve endings. A randomized placebo controlled study revealed that intravesical administration of liposome-encapsulated BoNT-A and TC-3 hydrogel embedded BoNT-A can improve urinary frequency, urgency, and reduce incontinence in patients with overactive bladders. A single-arm prospective study also revealed that intravesical administration of TC-3 hydrogel embedded BoNT-A can relieve bladder pain in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We recently administered suprapubic energy shock wave (ESW) after BoNT-A intravesical administration in six patients with IC/BPS. Although pain reduction and symptom improvement were not significant, immunochemical staining showed cleaved synaptosome-associated protein 25 in the bladder after the procedure. This suggests that ESW can promote passage of BoNT-A across the uroepithelium. In conclusion, using vehicles to intra-vesically deliver BoNT-A for functional bladder disorders is promising. Further studies are necessary to confirm the efficacy and explore novel applications. Full article
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