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

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.     

Long-Term Efficacy and Safety of Repeated Intravescial OnabotulinumtoxinA Injections Plus Hydrodistention in the Treatment of Interstitial Cystitis/Bladder Pain Syndrome

Intravesical onabotulinumtoxinA (BoNT-A) injection can relieve symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), but lacks sustainability. Repeated injections have been shown to provide a superior outcome to a single injection, but data on long-term efficacy and safety is limited. In this prospective study, we enrolled patients with refractory IC/BPS, and treated them with 100 U of BoNT-A injection plus hydrodistention followed by repeated injections every six months for up to two years or until the patient wished to discontinue. A “top-up” dose was offered after the fourth injection. Of these 104 participants, 56.7% completed four BoNT-A injections and 34% voluntarily received the fifth injection due to exacerbated IC symptoms. With a follow-up period of up to 79 months, O’Leary-Sant symptom and problem indexes (ICSI, ICPI, OSS), pain visual analogue scale (VAS) functional bladder capacity, frequency episodes, and global response assessment (GRA) all showed significant improvement (p < 0.0001). Those who received repeated injections had a better success rate during the long-term follow-up period. The incidence of adverse events did not rise with the increasing number of BoNT-A injections. A higher pre-treatment ICSI and ICPI score was predictive for successful response to repeated intravesical BoNT-A injections plus hydrodistention.     

Ultrasound-Guided Injection of Botulinum Toxin Type A for Piriformis Muscle Syndrome: A Case Report and Review of the Literature

Piriformis muscle syndrome (PMS) is caused by prolonged or excessive contraction of the piriformis muscle associated with pain in the buttocks, hips, and lower limbs because of the close proximity to the sciatic nerve. Botulinum toxin type A (BoNT-A) reduces muscle hypertonia as well as muscle contracture and pain inhibiting substance P release and other inflammatory factors. BoNT-A injection technique is important considering the difficult access of the needle for deep location, the small size of the muscle, and the proximity to neurovascular structures. Ultrasound guidance is easy to use and painless and several studies describe its use during BoNT-A administration in PMS. In the present review article, we briefly updated current knowledge regarding the BoNT therapy of PMS, describing also a case report in which this syndrome was treated with an ultrasound-guided injection of incobotulinumtoxin A. Pain reduction with an increase of hip articular range of motion in this patient with PMS confirmed the effectiveness of BoNT-A injection for the management of this syndrome.     

Botulinum toxin in the treatment of OAB, BPH, and IC

Botulinum neurotoxins (BoNTs) are well known for their ability to potently and selectively disrupt and modulate neurotransmission. BoNT is currently undergoing regulatory evaluation for urological disorders in the United States and the European Union and is not FDA approved for urologic use. Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) are common urologic conditions characterized by urinary frequency, urgency, nocturia, urge incontinence and, in the case of BPH, decreased urine flow that are currently being evaluated in clinical trials with BoNT-A. Interstitial cystitis (IC) is a chronic condition in which patients describe urinary frequency, urgency and associated bladder/pelvic pain. In the two former conditions, BoNT-A is currently being evaluated in Phase II or Phase III clinical trials as a therapeutic agent. Evidence for BoNT in the treatment of IC is limited to small case series. The purpose of this article is to provide up to date clinical evidence regarding the use of BoNT to treat these three urologic problems. For the sake of clarity, BoNT-A describes the use of Botox^® unless otherwise specified. In addition, when describing OAB, two sub-populations exist: those with OAB of neurogenic origin (NDO) and those with OAB of unknown (idiopathic) origin (IDO).     

O’Leary-Sant Symptom Index Predicts the Treatment Outcome for Onabotulinumtoxin A Injections for Refractory Interstitial Cystitis/Bladder Pain Syndrome

Although intravesical injection of onabotulinumtoxinA (BoNT-A) has been proved promising in treating patients with interstitial cystitis/bladder pain syndrome (IC/BPS), what kind of patients that may benefit from this treatment remains unclear. This study investigated the predictors for a successful treatment outcome. Patients with IC/BPS who failed conventional treatments were enrolled to receive intravesical injection of 100 U of BoNT-A immediately followed by hydrodistention. Variables such as O’Leary-Sant symptom and problem indexes (ICSI and ICPI), pain visual analogue scale (VAS), functional bladder capacity (FBC), voiding diary, and urodynamic parameters were measured at baseline and six months after treatment. A global response assessment (GRA) ≥ 2 at six months was defined as successful. There were101 patients enrolled. Significant improvements were observed in mean ICSI, ICPI, OSS (ICSI + ICPI), pain VAS, FBC, frequency, nocturia and GRA at six months after BoNT-A injections (all p < 0.05). The successful rate at six months was 46/101 (45.54%). Multivariate logistic regression revealed the baseline ICSI (odds ratio = 0.770, 95% confidence interval = 0.601–0.989) was the only predictor for a treatment outcome. ICSI ≥ 12 was the most predictive cutoff value for a treatment failure, with a ROC area of 0.70 (sensitivity = 69.1%, specificity = 60.9%).     

广泛全子宫切除术后围术期盆底肌肉功能锻炼对膀胱功能恢复的影响

目的 探讨盆底肌肉功能锻炼对广泛性全宫切除术后患者膀胱功能恢复的影响.方法 对我院从2009~2012年收治的93例子宫颈癌行广泛全子宫切除术后患者围术期进行一般护理及盆底肌肉训练.比较其尿潴留及尿路感染的发生率.结果 实行了盆底肌肉功能锻炼的患者组,其发生尿潴留及尿路感染的几率与未进行盆底肌肉功能锻炼的患者组差别显著,盆底肌肉功能锻炼组发生尿潴留及尿路感染发生率分别为19.6%、25.5%.对照组尿潴留及尿路感染的发生率分别为23.8%、35.7%.两组尿潴留及尿路感染发生率比较,差异具有统计学意义(P<0.05).结论 对广泛全子宫切除术患者进行盆底肌肉功能锻炼对膀胱功能恢复有显著影响,能大大降低尿潴留及尿路感染的发生率.     

妇女慢性盆腔痛妇科原因浅析

目的探讨妇女慢性盆腔痛妇科常见原因。方法将2002年1月～2003年1月于门诊妇科就诊的慢性盆腔痛病人270例作研究对象,寻找引起盆腔疼痛的原因。结果采用X2检验进行分析。妇女慢性盆腔痛的发生率为43%,其妇科常见原因前三位是:炎症占55.56%,盆腔淤血综合症占25.93%,子宫内膜异位征占10.00%。前两者在是否结扎、宫颈(腔)操作及年龄、妊娠史方面比较有显著性差异(P<0.05)。结论慢性妇科盆腔痛常发生于育龄妇女,其常见妇科原因为炎症、盆腔淤血综合征及子宫内膜异位征,孕产频繁、结扎、宫颈(腔)操作等有可能诱发本病。     

Adverse Events of Intravesical OnabotulinumtoxinA Injection between Patients with Overactive Bladder and Interstitial Cystitis—Different Mechanisms of Action of Botox on Bladder Dysfunction?

Intravesical onabotulinumtoxinA (BoNT-A) injections have been proposed to treat both overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) in patients with refractory conditions. We compared adverse events (AEs) after BoNT-A treatment between IC/BPS and OAB in women. IC/BPS patients who failed conventional treatments were enrolled to receive suburothelial injections of BoNT-A (100 U) followed by hydrodistention. Age matched OAB female patients refractory to antimuscarinic agents underwent BoNT-A (100 U) injections. The bladder capacity, maximum flow rate (Qmax), post-void residual (PVR), and voiding efficiency (VE) at baseline, 3 and 6 months, and the post-treatment AEs were analyzed between groups. Finally, 89 IC/BPS and 72 OAB women were included. In the OAB group, the bladder capacity and PVR increased, and VE decreased significantly at three and six months after BoNT-A treatment. In the IC/BPS group, the Qmax increased significantly at six months. There were significant differences in changes of capacity, Qmax, PVR and VE between the two groups. Moreover, OAB patients suffered more frequently from events of hematuria, UTI, and large PVR (>200 mL), but less frequently from events of straining to void. In conclusion, OAB women had higher PVR volume and lower VE than those in IC/BPS after BoNT-A injections. These results imply that the bladder contractility of OAB patients are more susceptible to BoNT-A, which might reflect the different mechanisms of action of Botox on bladder dysfunction. Further investigations to confirm this hypothesis are warranted.     

New agents for the medical treatment of interstitial cystitis

Interstitial cystitis (IC) is a painful, sterile, disorder of the urinary bladder characterised by urgency, frequency, nocturia and pain. IC occurs primarily in women but also in men with recent findings indicating that chronic, abacterial prostatitis may be a variant of this condition. The prevalence of IC has ranged from about 8 - 60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner’s ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Symptoms of IC are exacerbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and many publications showing a high number of activated bladder mast cells. Increasing evidence suggests that neurogenic inflammation and/or neuropathic pain is a major component of IC pathophysiology. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpolysulphate (PPS). New treatments focus on the combined use of drugs that modulate bladder sensory nerve stimulation (neurolytic agents), inhibit neurogenic activation of mast cells, or provide urothelial cytoprotection, together with new drugs with anti-inflammatory activity.     

New agents for the medical treatment of interstitial cystitis

Interstitial cystitis (IC) is a painful, sterile, disorder of the urinary bladder characterised by urgency, frequency, nocturia and pain. IC occurs primarily in women but also in men with recent findings indicating that chronic, abacterial prostatitis may be a variant of this condition. The prevalence of IC has ranged from about 8 - 60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner's ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Symptoms of IC are exacerbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and many publications showing a high number of activated bladder mast cells. Increasing evidence suggests that neurogenic inflammation and/or neuropathic pain is a major component of IC pathophysiology. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpolysulphate (PPS). New treatments focus on the combined use of drugs that modulate bladder sensory nerve stimulation (neurolytic agents), inhibit neurogenic activation of mast cells, or provide urothelial cytoprotection, together with new drugs with anti-inflammatory activity.     

Interstitial cystitis: bladder pain and beyond

Background: Interstitial cystitis is characterized by over 6 months of chronic pain, pressure and discomfort felt in the lower pelvis or bladder. It is often relieved with voiding, along with daytime frequency and nocturia in the absence of a urinary tract infection. Interstitial cystitis occurs primarily in females including adolescents and its diagnosis is still one of exclusion. It is now recognized as a serious medical condition associated with significant disability. Objective: The aim of this paper was to review the pathogenesis and treatment of interstitial cystitis with emphasis on new pathogenetic trends and therapeutic modalities. Methods: About 713 mostly original papers were reviewed in Medline from 1990 to August. 2008. All authors independently reviewed the literature. Large, double-blind, placebo-controlled, clinical trials were few and the medical histories of the patients used varied considerably making conclusions difficult. Promising pilot trials turned out mostly negative on follow-up. Results: Increasing evidence of co-morbid diseases, neurogenic inflammation and the effect of stress are promising as new targets for pathophysiology. No new effective treatments have emerged. Oral pentosanpolysulfate, amitriptyline, hydroxyzine and quercetin, as well as intravesical heparin/bicarbonate/lidocaine solutions, are still used with variable success. Some pilot open-label trials presented encouraging findings. Conclusion: Interstitial cystitis contributes substantially to chronic pelvic pain and to poor quality of life. Oral or intravesical administration of solutions containing sodium hyaluronate, chondroitin sulfate and quercetin to both reduce bladder inflammation and ‘replenish’ the glycosaminoglycan layer should be tried. There is a clear need for therapeutic modalities. New potential translational research areas are suggested.     

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

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.     

Normalization of proliferation and tight junction formation in bladder epithelial cells from patients with interstitial cystitis/painful bladder syndrome by d-proline and d-pipecolic acid derivatives of antiproliferative factor

Interstitial cystitis/painful bladder syndrome is a chronic bladder disorder with epithelial thinning or ulceration, pain, urinary frequency and urgency, for which there is no reliably effective therapy. We previously reported that interstitial cystitis/painful bladder syndrome bladder epithelial cells make a glycopeptide antiproliferative factor or 'APF' (Neu5Acα2-3Galβ1-3GalNAcα-O-TVPAAVVVA) that induces abnormalities in normal cells similar to those in interstitial cystitis/painful bladder syndrome cells in vitro, including decreased proliferation, decreased tight junction formation, and increased paracellular permeability. We screened inactive APF derivatives for their ability to block antiproliferative activity of asialylated-APF ('as-APF') in normal bladder cells and determined the ability of as-APF-blocking derivatives to normalize tight junction protein expression, paracellular permeability, and/or proliferation of interstitial cystitis/painful bladder syndrome cells. Only two of these derivatives [Galβ1-3GalNAcα-O-TV-(d-pipecolic acid)-AAVVVA and Galβ1-3GalNAcα-O-TV-(d-proline)-AAVVVA] blocked as-APF antiproliferative activity in normal cells (p < 0.001 for both). Both of these antagonists also 1) significantly increased mRNA expression of ZO-1, occludin, and claudins 1, 4, 8, and 12 in interstitial cystitis/painful bladder syndrome cells by qRT-PCR; 2) normalized interstitial cystitis/painful bladder syndrome epithelial cell tight junction protein expression and tight junction formation by confocal immunofluorescence microscopy; and 3) decreased paracellular permeability of (14) C-mannitol and (3) H-inulin between confluent interstitial cystitis/painful bladder syndrome epithelial cells on Transwell plates, suggesting that these potent APF antagonists may be useful for the development as interstitial cystitis/painful bladder syndrome therapies.     

Potential Effect of Liposomes and Liposome-Encapsulated Botulinum Toxin and Tacrolimus in the Treatment of Bladder Dysfunction

Bladder drug delivery via catheter instillation is a widely used treatment for recurrence of superficial bladder cancer. Intravesical instillation of liposomal botulinum toxin has recently shown promise in the treatment of overactive bladder and interstitial cystitis/bladder pain syndrome, and studies of liposomal tacrolimus instillations show promise in the treatment of hemorrhagic cystitis. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core that can encapsulate hydrophilic and hydrophobic drug molecules to be delivered to cells via endocytosis. This review will present new developments on instillations of liposomes and liposome-encapsulated drugs into the urinary bladder for treating lower urinary tract dysfunction.     

腹腔镜诊治慢性盆腔疼痛25例临床分析

目的了解非洲博茨瓦纳妇女慢性盆腔疼痛的病因,探讨腹腔镜对诊治慢性盆腔疼痛的临床价值。方法收集2006年6月～2007年6月在非洲博茨瓦纳玛丽娜公主医院行腹腔镜诊治的25例慢性盆腔疼痛病例并进行回顾性分析。结果25例患者中慢性盆腔炎16例(64%),子宫内膜异位症4例(16%),盆腔淤血综合征2例(8%)。术后17例患者疼痛消失,6例明显好转。结论慢性盆腔炎、子宫内膜异位症和盆腔淤血综合征是博茨瓦纳妇女慢性盆腔疼痛的主要病因,腹腔镜诊治慢性盆腔疼痛有良好效果。     

腹腔镜诊治慢性盆腔痛72例临床分析

目的评价腹腔镜诊治慢性盆腔痛的效果。方法对腹腔镜诊治的72例慢性盆腔痛的患者进行回顾分析,比较其临床表现、术中所见、腹腔镜下实施的手术及术后随访资料。结果 72例患者中,腹腔镜证实有病理改变和解剖改变的70例,占97.22%;其中,子宫内膜异位症有35例(48.61%),盆腔粘连23例(31.94%),慢性盆腔炎后遗症9例(12.50%),盆腔静脉淤血症3例(4.17%),盆腔未发现病变2例(2.78%)。术后疼痛症状完全缓解37例(51.39%),部分缓解29例(40.28%),未缓解6例(8.33%)。结论腹腔镜诊断慢性盆腔痛是一种较优越的方法,在寻找病因的同时可给予适当的治疗,值得推广使用。     

Management of patients with interstitial cystitis or chronic pelvic pain of bladder origin: a consensus report

BACKGROUND: Interstitial cystitis (IC) remains a challenging disease to treat, but increased awareness, better diagnostic tools, and effective pharmacologic agents can help non-urologists successfully manage this condition. Interstitial cystitis is much more prevalent than previously thought and is often misdiagnosed. Left untreated, IC can have a deleterious effect on the quality of life of the affected individual. In-office symptom-based techniques have been developed to screen for the presence of IC in both women and men presenting with symptoms of chronic pelvic pain (CPP) or chronic prostatitis (CP), and effective pharmacologic treatments exist that can provide acute and long-term symptom relief. Individual patient response to therapy varies, with some patients taking up to several months to achieve an optimal therapeutic response. To optimize patient response, a comprehensive algorithm for the diagnosis and management of IC should be utilized. Symptoms and progress should be assessed at each follow-up visit and changes in therapy made accordingly. Patients should be encouraged to learn as much as possible about IC and to take charge of the management of symptoms using their physician for guidance in decision making. The importance of this aspect of therapy should be reinforced at each subsequent visit. The entire office staff also has an important role in understanding and acknowledging each patient's pain and frustration as well as in providing support and education about IC. SCOPE: This paper presents recommendations from a multidisciplinary panel for the evaluation, diagnosis, treatment, and follow-up care of patients with IC or CPP of bladder origin.     

腹腔镜与阴式子宫全切术对盆底功能的影响

目的：探讨经阴道子宫切除术（TVH）、腹腔镜下子宫切除术（LTH）、与腹腔镜辅助下阴式子宫全切术（LAVH）三种术式对盆底功能的影响。方法：216例非脱垂子宫全切术患者随机分为3组,分别接受TVH、LTH与LAVH手术。术后系统随访。评价术后6个月时的阴道脱垂程度、膀胱和直肠膨出程度、压力性尿失禁情况和盆底肌肉肌力。结果：TVH组、LTH组、LAVH组阴道脱垂分别为2例（2.8%）、1例（1.4%）、1例（1.4%）（P〉0.05）;膀胱和直肠膨出分别为3例（4.2%）、1例（1.4%）、2例（2.8%）（P〉0.05）;压力性尿失禁分别为4例（5.6%）、2例（2.8%）、3例（4.2%）（P〉0.05）;TVH组盆底肌肉肌力最弱（P〈0.05）,而LTH组与LAVH组两组间肌力相似。结论：3种子宫切除术对盆底功能影响均较小;而腹腔镜下子宫切除术与腹腔镜辅助下阴式子宫全切术对盆底肌肉肌力影响更小;而腹腔镜辅助下阴式子宫全切术难度较小,更值得推荐。     

理气化瘀汤治疗气滞血瘀型慢性骨盆疼痛综合征的临床研究

目的 探讨理气化瘀汤治疗气滞血瘀型慢性骨盆疼痛综合征的临床疗效及安全性。 方法 将72例气滞血瘀型慢性骨盆疼痛综合征患者随机分为中药组、西药组和中西结合组。中药组口服理气化瘀汤,西药组口服盐酸特拉唑嗪,中西结合组口服理气化瘀汤和盐酸特拉唑嗪。治疗21 d后,观察慢性前列腺炎症状指数评分(NIH-CPSI评分表疼痛、排尿症状部分)、前列腺液常规等。结果 中西送结合组及中药组的前列腺疼痛症状评分和前列腺常规较西药组有统计学意义(P＜0.05),两组排尿症状积分治疗前后均有统计学意义(P＜0.05)。同时两组病例均未出现明显的不良反应。结论 中医药对慢性骨盆疼痛综合征有效,尤其是对疼痛及排尿症状的疗效明显。