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

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 22941

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Prof. Francisco Cruz

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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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Department of Urology, Hualien Tzu Chi Hospital, Tzu Chi Medical Foundation, Buddhist Tzu Chi University, Hualien, Taiwan
Interests: botulinum neurotoxin; neurourology; urodynamics; female urology; stress urinary; incontinence; LUTS
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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

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11 pages, 264 KiB

Open AccessArticle

Video-Urodynamic Characteristics and Predictors of Switching from Botulinum Neurotoxin a Injection to Augmentation Enterocystoplasty in Spinal Cord Injury Patients

by Chih-Chieh Lin and Hann-Chorng Kuo

Toxins 2022, 14(1), 47; https://doi.org/10.3390/toxins14010047 - 10 Jan 2022

Cited by 5 | Viewed by 1826

Abstract

Botulinum neurotoxin type A (BoNT-A) injection and augmentation enterocystoplasty (AE) are alternative and effective management strategies for neurogenic detrusor overactivity (NDO) refractory to pharmacotherapy. A great majority of patients with spinal cord injury (SCI) may, however, prefer BoNT-A injections to AE, due to the less invasive characteristics. In this study we evaluated the influence of various video-urodynamic study (VUDS) parameters in SCI patients who continuously received repeat BoNT-A detrusor injections or switched to AE to improve their bladder conditions. We compared the changes in the urodynamic parameters before and after each mode of treatment. In this retrospective study, all SCI patients with refractory NDO who had received at least one BoNT-A injection were enrolled. VUDS was performed before and after both BoNT-A injection and AE. All of the urodynamic parameters of the storage and micturition—including the bladder capacity of every sensation, maximal flow rate (Qmax), post-voiding residual volume, detrusor pressure at Qmax, and bladder contractility index—were recorded. A total of 126 patients, including 46 women and 80 men, with a mean age of 41.8 ± 13.1 years, were recruited for this study. All of the patients receiving either BoNT-A injection or AE had a statistically significant increase of bladder capacity at every time-point during filling and a decrease in detrusor pressure at Qmax during voiding. Patients who switched from BoNT-A to AE had greater improvements in their urodynamic parameters when compared with those who continued with BoNT-A injections. Accordingly, SCI patients receiving BoNT-A injections but experiencing few improvements in their urodynamic parameters should consider switching to AE to achieve a better storage function and bladder capacity. Full article

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

11 pages, 697 KiB

Open AccessArticle

Satisfaction with Detrusor OnabotulinumtoxinA Injections and Conversion to Other Bladder Management in Patients with Chronic Spinal Cord Injury

by Sheng-Fu Chen, Yuan-Hong Jiang, Jia-Fong Jhang and Hann-Chorng Kuo

Toxins 2022, 14(1), 35; https://doi.org/10.3390/toxins14010035 - 3 Jan 2022

Cited by 9 | Viewed by 2296

Abstract

This study investigated the satisfaction with continued detrusor Botox injections for urinary incontinence and conversion to other surgical procedures and bladder management procedures for neurogenic detrusor overactivity (NDO) in patients with chronic spinal cord injury (SCI). A total of 223 patients with chronic SCI underwent detrusor Botox 200U for urodynamically confirmed NDO and urinary incontinence. After initial detrusor Botox injections, patients opted to either continue detrusor Botox injections every six to nine months and on clean intermittent catheterization (CIC), switch to other bladder management procedures, or receive surgical procedures to improve their urinary incontinence, correct emergent complications, or have better voiding conditions without CIC. Urinary incontinence improvement rates and satisfaction with bladder management were assessed and compared between different subgroups, urodynamic parameters, and bladder management procedures. Finally, a total of 154 male and 69 female patients were included, among whom 56 (25.1%), 81 (36.3%), 51 (22.9%), and 35 (15.7%) showed a marked, moderate, mild, and no reduction in urinary incontinence, respectively. However, only 48.4% of the patients continued detrusor Botox injections over the mean follow-up period of seven years. Patients with cervical or thoracic SCI had fair incontinence improvement rates. The presence of high detrusor pressure and higher-grade bladder outlet resistance also predicted a decrease in incontinence. Although more than 50% of the patients switched to other bladder management procedures or received surgical treatment, 69.1% expressed satisfaction with their current status. This large cohort of patients with chronic SCI who received initial detrusor Botox injections revealed that only 48.4% continued with Botox injections. Those who received surgical procedures due to urological complications or demanded change in bladder management could achieve high satisfaction rates. Full article

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

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11 pages, 448 KiB

Open AccessArticle

Real-World Data Regarding Satisfaction to Botulinum Toxin A Injection into the Urethral Sphincter and Further Bladder Management for Voiding Dysfunction among Patients with Spinal Cord Injury and Voiding Dysfunction

by Cheng-Ling Lee, Jia-Fong Jhang, Yuan-Hong Jiang and Hann-Chorng Kuo

Toxins 2022, 14(1), 30; https://doi.org/10.3390/toxins14010030 - 2 Jan 2022

Cited by 10 | Viewed by 3133

Abstract

Purpose: This study aimed to investigate improvement in voiding condition after the initial botulinum toxin A (BoNT-A) injection into the urethral sphincter among patients with chronic spinal cord injury (SCI) and voiding dysfunction. Moreover, subsequent surgical procedures and bladder management were evaluated. Materials and Methods: From 2011 to 2020, 118 patients with SCI and dysuria who wanted to void spontaneously received their first BoNT-A injection at a dose of 100 U into the urethral sphincter. Improvement in voiding and bladder conditions after BoNT-A treatment were assessed. Next, patients were encouraged to continually receive BoNT-A injections into the urethral sphincter, convert to other bladder managements, or undergo surgery. After undergoing bladder management and surgical procedures, the patients were requested to report improvement in voiding condition and overall satisfaction to bladder conditions. Then, data were compared. Results: In total, 94 male and 24 female participants were included in this analysis. Among them, 51 presented with cervical, 43 with thoracic, and 24 with lumbosacral SCI. After BoNT-A injections into the urethral sphincter, 71 (60.2%) patients, including 18 (15.3%) with excellent, and 53 (44.9%) with moderate improvement, had significant improvement in voiding condition. Patients with cervical SCI (66.6%), detrusor overactivity and detrusor sphincter dyssynergia (72.0%), partial hand function (80.0%), and incomplete SCI (68.4%) had a better improvement rate than the other subgroups. Only 42 (35.6%) patients continually received treatment with BoNT-A injections into the urethral sphincter. Meanwhile, more than 60% of patients who converted their treatment to augmentation enterocystoplasty (n = 5), bladder outlet surgery (n = 25), BoNT-A injections into the detrusor muscle (n = 20), and medical treatment (n = 55) had moderate and marked improvement in voiding dysfunction and overall satisfaction. Discussion: Although BoNT-A injections into the urethral sphincter could improve voiding condition, only patients with SCI who presented with voiding dysfunction were commonly satisfied. Those whose treatments were converted to other bladder managements, which can promote urinary continence, or to surgical procedures, which can facilitate spontaneous voiding, had favorable treatment outcomes. Full article

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

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9 pages, 249 KiB

Open AccessArticle

Effectiveness and Safety of Intradetrusor OnabotulinumtoxinA Injection for Neurogenic Detrusor Overactivity and Overactive Bladder Patients in Taiwan—A Phase IV Prospective, Interventional, Multiple-Center Study (Restore Study)

by Chung-Cheng Wang, Eric Chieh-Lung Chou, Yao-Chi Chuang, Chih-Chieh Lin, Yu-Chao Hsu, Chun-Hou Liao and Hann-Chorng Kuo

Toxins 2021, 13(12), 911; https://doi.org/10.3390/toxins13120911 - 20 Dec 2021

Cited by 5 | Viewed by 3086

Abstract

We conducted a phase IV, pre/post multi-center study to evaluate the efficacy and safety of intradetrusor onabotulinumtoxinA injection in patients with neurogenic detrusor overactivity (NDO, n = 119) or overactive bladder (OAB, n = 215). Patients received either 200U (i.e., NDO) and 100U (i.e., OAB) of onabotulinumtoxinA injection into the bladder, respectively. The primary endpoint for all patients was the change in the PPBC questionnaire score at week 4 and week 12 post-treatment compared with baseline. The secondary endpoints were the changes in subjective measures (i.e., questionnaires: NBSS for patients with NDO and OABSS for those with OAB) at week 4 and week 12 post-treatment compared with baseline. Adverse events included symptomatic UTI, de novo AUR, gross hematuria and PVR > 350mL were recorded. The results showed that compared with baseline, PPBC (3.4 versus 2.4 and 2.1, p < 0.001) and NBSS (35.4 versus 20.4 and 18.1, p < 0.001) were significantly improved at 4 weeks and 12 weeks in NDO patients. In addition, compared with baseline, PPBC (3.5 versus 2.3 and 2.0, p < 0.001) and OABSS (9.1 versus 6.2 and 5.7, p < 0.001) were significantly improved at 4 weeks and 12 weeks in OAB patients. Eight (6.7%) had symptomatic UTI and 5 (4.2%) had de novo AUR in NDO patients. Twenty (9.3%) had symptomatic UTI but no de novo AUR in OAB patients. In conclusion, we found that intradetrusor onabotulinumtoxinA injections were safe and improved subjective measures related to NDO or OAB in our cohort. Full article

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

11 pages, 261 KiB

Open AccessEditor’s ChoiceArticle

Therapeutic Efficacy of Urethral Sphincteric Botulinum Toxin Injections for Female Sphincter Dysfunctions and a Search for Predictive Factors

by Yin-Chien Ou, Kuan-Hsun Huang, Hau-Chern Jan, Hann-Chorng Kuo, Yao-Lin Kao and Kuen-Jer Tsai

Toxins 2021, 13(6), 398; https://doi.org/10.3390/toxins13060398 - 2 Jun 2021

Cited by 10 | Viewed by 3026

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 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

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

10 pages, 1561 KiB

Open AccessArticle

Therapeutic Effects of Urethral Sphincter Botulinum Toxin A Injection on Dysfunctional Voiding with Different Videourodynamic Characteristics in Non-Neurogenic Women

by Yuan-Hong Jiang, Cheng-Ling Lee, Sheng-Fu Chen and Hann-Chorng Kuo

Toxins 2021, 13(5), 362; https://doi.org/10.3390/toxins13050362 - 19 May 2021

Cited by 7 | Viewed by 2576

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 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

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

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Review

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14 pages, 653 KiB

Open AccessReview

Botulinum Toxin Injection for Medically Refractory Neurogenic Bladder in Children: A Systematic Review

by Shu-Yu Wu, Shang-Jen Chang, Stephen Shei-Dei Yang and Chun-Kai Hsu

Toxins 2021, 13(7), 447; https://doi.org/10.3390/toxins13070447 - 28 Jun 2021

Cited by 17 | Viewed by 3011

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 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

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

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8 pages, 673 KiB

Open AccessReview

Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders

by Jia-Fong Jhang and Hann-Chorng Kuo

Toxins 2021, 13(5), 359; https://doi.org/10.3390/toxins13050359 - 18 May 2021

Cited by 9 | Viewed by 2882

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 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

(This article belongs to the Special Issue Botulinum Toxins: Old and New Applications in Humans and Animals for the Treatment of Lower Urinary Tract Conditions)

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