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.     

Botulinum toxin A for the Treatment of Overactive Bladder

The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.     

Alternative use of botulinum toxin in urology

Botulinum toxin A is used in the treatment of lower urinary tract symptoms due to detrusor sphincter dysynergia and detrusor hyper-reflexia (neurogenic detrusor deficiency). The toxin acts by producing paralysis of muscle tissue and has been shown to be safe and effective in the treatment of conditions caused by increased muscle tonicity and spasticity. Here the literature is reviewed chronologically, the established and emerging indications for the urological use of botulinum toxin evaluated and future applications are also considered.     

Inhibitory effect of anticholinergics on the contraction of isolated caprine urinary bladder detrusor muscle

1. This study investigated whether four anticholinergics which are not clinically used for relaxing the urinary bladder detrusor muscle inhibit the contraction of isolated caprine (goat) detrusor muscle: cyclopentolate (100 nm ), homatropine (5 μm ), ipratropium (500 nm ) and valethamate (1 μm ). 2. The effects of these anticholinergics were compared with tolterodine (3 μm ), an anticholinergic clinically used for relaxing the detrusor muscle. The inhibitory effect of each of these five anticholinergics was studied on six strips of caprine detrusor muscle made to contract with 100 μm acetylcholine (ACh) by determining the percent inhibition of height of contraction and the area under the contractile curve (AUC). 3. It was found that all five anticholinergics inhibited the ACh‐induced contraction of the caprine detrusor and that this inhibition was reversed by raising the concentration of ACh. Hence, these four anticholinergics, like tolterodine, may be useful in managing clinical conditions that require relaxation of the detrusor muscle.     

Tramadol inhibits the contractility of isolated caprine detrusor muscle

1 The atypical opioid analgesic tramadol has been shown to provide beneficial clinical and urodynamic effects in patients with detrusor overactivity. The effect of tramadol on isolated detrusor muscle has not been studied. This study investigated the ability of tramadol to inhibit acetylcholine (ACh)‐induced contractility of the isolated caprine (goat) detrusor muscle. The effect of three concentrations (30, 100 and 300 μm ) of tramadol on 10 caprine detrusor strips contracted by the addition of 100, 200 or 400 μm ACh was studied. The sensitivity of tramadol‐induced inhibition of ACh responses to treatment with the β‐adrenoceptor antagonist propranolol (1 μm ) and the opioid receptor antagonist naloxone (100 μμ ) was also studied. 2 Tramadol caused a concentration‐dependent inhibition of ACh‐induced detrusor contraction that was reversed by raising the concentration of ACh. Propranolol, but not naloxone, reversed the tramadol‐induced inhibition of contractions to ACh in the detrusor. 3 These results suggest that tramadol inhibits ACh‐induced contractility of the isolated detrusor. They also suggest that tramadol does so by an indirect anticholinergic mechanism involving the stimulation of β‐adrenoceptors. Tramadol may be useful in managing clinical conditions requiring relaxation of the detrusor muscle. Although the concentrations of tramadol needed to relax the detrusor were relatively high, these could be clinically attained via intravesical administration.     

Inhibitory Effect of Curcumin on the Contractility of Isolated Caprine Detrusor Muscle

Curcumin is a naturally occurring compound which has been used in traditional medicine in India for a long time. This study investigated the ability of curcumin to inhibit the contractility of isolated caprine (goat) detrusor muscle. The ability of three concentrations of curcumin (30, 100 and 300 µM) to inhibit the 100 µM acetylcholine-induced contractility of the isolated caprine urinary bladder detrusor muscle was investigated. The effect of raising the concentration of acetylcholine from 100, 200 and 400 µM to overcome the curcumin-induced inhibition of detrusor contractility and the effects of the reversal agents tetraethylammonium, a potassium channel blocker (100 µM), glibenclamide, an ATP-sensitive potassium channel blocker (10 µM), and propranolol, a beta adrenergic receptor blocker (1 µM), on the inhibitory effect of detrusor contractility was also studied. Curcumin caused a concentration-dependent inhibition of acetylcholine-induced contractility of the isolated detrusor muscle which was statistically significant at all three concentrations of curcumin used. This inhibition was partially overcome by raising the concentration of ACh to 200 and 400 µM. The inhibition was overcome by the concurrent administration of tetraethylammonium. Glibenclamide reversed the inhibitory effect of 100 µM curcumin, but not that of 300 µM curcumin. Propranolol reversed the inhibitory effect of 100 µM curcumin but not that of 300 µM curcumin. These results suggest that curcumin inhibited the contractions of the isolated detrusor muscle. The results further suggest that the inhibitory effect is mediated by various mechanisms: stimulation of beta adrenergic receptors; an anticholinergic effect; and the opening of ATP-sensitive potassium channels.     

Does Reduction of Number of Intradetrusor Injection Sites of aboBoNTA (Dysport?) Impact Efficacy and Safety in a Rat Model of Neurogenic Detrusor Overactivity?

Intradetrusor injections of Botulinum toxin A—currently onabotulinumtoxinA—is registered as a second-line treatment to treat neurogenic detrusor overactivity (NDO). The common clinical practice is 30 × 1 mL injections in the detrusor; however, protocols remain variable and standardization is warranted. The effect of reducing the number of injection sites of Dysport^® abobotulinumtoxinA (aboBoNTA) was assessed in the spinal cord-injured rat (SCI). Nineteen days post-spinalization, female rats received intradetrusor injections of saline or aboBoNTA 22.5 U distributed among four or eight sites. Two days after injection, continuous cystometry was performed in conscious rats. Efficacy of aboBoNTA 22.5 U was assessed versus aggregated saline groups on clinically-relevant parameters: maximal pressure, bladder capacity, compliance, voiding efficiency, as well as amplitude, frequency, and volume threshold for nonvoiding contractions (NVC). AboBoNTA 22.5 U significantly decreased maximal pressure, without affecting voiding efficiency. Injected in four sites, aboBoNTA significantly increased bladder capacity and compliance while only the latter when in eight sites. AboBoNTA significantly reduced NVC frequency and amplitude. This preclinical investigation showed similar inhibiting effects of aboBoNTA despite the number of sites reduction. Further studies are warranted to optimize dosing schemes to improve the risk-benefit ratio of BoNTA-based treatment modalities for NDO and further idiopathic overactive bladder.     

The role of botulinum toxin in neurourology

Botulinum toxin is a presynaptic neuromuscular blocking agent that induces a selective and reversible muscle weakness of up to several months when injected intramuscularly in minute quantities. Different medical disciplines have applied the toxin to treat mainly muscular hypercontraction. For neurourologically impaired patients, the reported successful treatment of neurogenic detrusor overactivity and detrusor sphincter dyssynergia with botulinum-A toxin is a promising alternative option to conservative medication or surgery. This review of the literature presents current indications, techniques for and results of the use of botulinum toxin in neurourologically impaired patients and aims to give an insight into this new therapeutic option.     

Muscarinic receptors of the urinary bladder: detrusor,urothelial and prejunctional

1. The parasympathetic nervous system is responsible for maintaining normal bladder function, contracting the bladder smooth muscle (detrusor) and relaxing the bladder outlet during micturition. 2. Contraction of the bladder involves direct contraction via M3 receptors and an indirect 're-contraction' via M2-receptors whereby a reduction in adenylate cyclase activity reverses the relaxation induced by beta-adrenoceptor stimulation. 3. Muscarinic receptors are also located on the epithelial lining of the bladder (urothelium) where they induce the release of a diffusible factor responsible for inhibiting contraction of the underlying detrusor smooth muscle. The factor remains unidentified but is not nitric oxide, a cyclooxygenase product or adenosine triphosphate. 4. Finally, muscarinic receptors are also located prejunctionally in the bladder on cholinergic and adrenergic nerve terminals, where M1-receptors facilitate transmitter release and M2 or M4-receptors inhibit transmitter release. 5. In pathological states, changes may occur in these receptor systems resulting in bladder dysfunction. Muscarinic receptor antagonists are the main therapeutic agents available for treatment of the overactive bladder, but whether their therapeutic effect involves actions at all three locations (detrusor, prejunctional, urothelial) has yet to be established.     

Bladder instability: a re‐appraisal of classical experimental approaches and development of new therapeutic strategies

1 Despite the growing social interest in human urinary tract disorders, the aetiology of detrusor instability remains poorly understood. Myogenic and neural impairment of detrusor activity caused by CNS or autonomic injuries can results in dysfunctions of normal voiding of the bladder such as urinary incontinence. 2 The contractility of human detrusor smooth muscle is critically dependent on acetylcholine‐induced muscarinic receptor activation. Biochemical and functional in vivo and in vitro studies suggest the presence of an heterogeneous population of muscarinic receptor subtypes (M₁–M₄) localized at muscular and neutral sites. There is increasing evidence on the prejunctional auto‐ and hetero‐regulation of acetylcholine release from parasympathetic nerve endings in modulating detrusor muscle contraction during micturition. 3 Activation of P2X purinoreceptors closely associated with the parasympathetic varicosities seems to be implicated to varying extent in the contractility in normal or instable human detrusor. Interestingly, P2X₁ subtype expression on smooth muscle increases considerably in the symptomatically obstructed bladder. A striking absence of P2X₃ and P2X₅ subtypes was observed in the cholinergic innervation of detrusor from patients with urgent incontinence. Thus, it is likely that alteration of the neural acetylcholine control can play a critical role in pathological states. 4 If the failures in storage and voiding can be recognized urodynamically, considerable difficulties remain in investigating the underlying functional changes especially because the study of the pathophysiology requires techniques that can be justified in animals but not in humans. 5 Recently, to solve this problem an alternative technique using human smooth muscle cells in culture has been developed. Human cell lines may be relevant in investigating the molecular pathways in physiological and pathological conditions. 6 The potential development of novel molecular therapeutic strategies such as gene therapy and tissue engineering is also discussed.     

Phorbol ester-induced contractions of mouse detrusor muscle are inhibited by nifedipine

The effects of phorbol esters on contractions of detrusor strips isolated from mouse urinary bladder were studied. β-Phorbol-12,13-dibutyrate (β-PDBu, 10 nM) significantly enhances both the neurogenic and myogenic detrusor contractions to a similar extent. By contrast, an inactive isoform of protein kinase C (PKC) stimulation, α- phorbol-12,13-dibutyrate (100 nM) has no such enhancing effect on the muscle contraction. The effect of β-PDBu was dependent on the extracellular Ca²⁺ concentration. Nifedipine (0.3 μM, a L-type Ca²⁺ channel blocker), staurosporine (1 μM) and bisindolylmaleimide I ( μM, a selective PKC inhibitor) but not ω-conotoxin GVIA (an N-type Ca²⁺ channel blocker) abolished the enhancing effect of β-PDBu. In other words, β-PDBu failed to augment the nifedipine-insensitive component of the muscle contraction. Moreover, β-PDBu not only enhances the muscle response induced by exogenous agonists (acetylcholine or ATP) and KCl but also increases the resting tone of detrusor muscle, an effect which is also inhibited by nifedipine and bisindolylmaleimide I. From these findings, it is concluded that the enhancing effect of β-PDBu is due to activation of the L-type Ca²⁺ channel through phosphorylation by protein kinase C. This allows more Ca²⁺ influx from the extracellular medium, leading to an increase in the contractions of the mouse detrusor muscle. Received: 29 October 1997 / Accepted; 17 February 1998     

Bladder contractility is mediated by different K+ channels in the urothelium and detrusor smooth muscle

The roles played by K(+) channels in the urothelium (UE) and detrusor smooth muscle (DSM) in regulating agonist-induced bladder contraction is not known at present. Thus, the effects in carbachol (CCh)-induced contraction in UE-intact (+UE) and UE-denuded (-UE) rat detrusor strips pretreated with K(+)-channel blockers were investigated here. The K(+)-channel blockers used were 4-aminopyridine (4-AP), glibenclamide (Glib), iberiotoxin (IbTx), charybdotoxin (ChTx), and apamin. In the absence of K(+)-channel blockers, control CCh-induced contractions were more potent in -UE than +UE strips. Treatment with IbTx and apamin resulted in more potent CCh-induced contractions in +UE strips. In -UE strips, CCh potency was increased by ChTx and Glib, but decreased by 4-AP. Different K(+) channels in the UE and DSM were thus involved in regulating bladder contractions. Contractile mediatory function of these channels, specific to the UE or DSM, may be potential drug targets in the management of bladder disorders.     

BoNT/A1 Secondary Failure for the Treatment of Neurogenic Detrusor Overactivity: An Ex Vivo Functional Study

Management of neurogenic detrusor overactivity (NDO) remains a clinical priority to improve patients’ quality of life and prevent dramatic urological complications. Intradetrusor injection of onabotulinumtoxinA (BoNT/A1, botulinum neurotoxin A1) is approved as second therapeutic line in these patients, demonstrating a good efficacy. However, a loss of its efficacy over time has been described, with no clear understanding of the underlying mechanisms. This paper aims at shedding new light on BoNT/A1 secondary failure in NDO through functional and structural analysis. Three groups of patients (either non-NDO, NDO with no toxin history or toxin secondary failure) were investigated using an ex vivo bladder strip assay. Detrusor strips were tensed in organ baths and submitted to electrical field stimulation to generate contractions. Recombinant BoNT/A1 was then added at various concentrations and contractions recorded for 4 h. Histology exploring BoNT/A1 targets, fibrosis and neuronal markers was also used. Detrusor strips from patients with BoNT/A1 secondary failure displayed a smaller sensitivity to toxin ex vivo at 3 nM compared to the other groups. Histological evaluation demonstrated the presence of cleaved Synaptosomal-Associated Protein, 25 kDa (c-SNAP25) in the detrusor from the toxin-secondary failure population, indicating some remaining in vivo sensitivity to BoNT/A1 despite the therapeutic escape. Moreover, residual c-SNAP25 did not affect parasympathetic-driven contractions observed ex vivo. This study confirms the slightly lower efficacy of BoNT/A1 in the BoNT/A1 secondary failure NDO group, suggesting that the escape from BoNT/A1 efficacy in NDO occurs at least at the parasympathetic level and could imply compensatory mechanisms for detrusor contraction.     

The minor population of M3‐receptors mediate contraction of human detrusor muscle in vitro

1 The objective was to determine the role of muscarinic receptor subtypes in mediating contraction of the human detrusor smooth muscle in vitro. 2 Contractile responses of human detrusor muscle strips to carbachol were obtained in the absence and presence of a range of muscarinic antagonists (pirenzepine, methoctramine, 4‐diphenylacetoxy‐N‐methyl piperidine methiodide (4‐DAMP), tropicamide, oxybutynin and tolterodine). Affinity estimates (pK_B values) were calculated for the antagonists and correlated with values at the cloned muscarinic receptor subtypes quoted in the literature. 3 Pirenzepine, methoctramine and tropicamide drugs that have high affinities at M₁, M₂ and M₄‐receptors, respectively, all had low affinities on the human detrusor (pK_B values of 6.8, 6.9 and 6.5, respectively), whilst the M₃‐selective antagonist 4‐DAMP had a high affinity (9.5). Schild plots for all four antagonists had slopes of unity indicating an action at a single receptor. Oxybutynin and tolterodine also acted as competitive antagonists with affinity estimates of 7.6 and 8.1, respectively. 4 When the antagonist affinities obtained on the bladder were plotted against the values published for these antagonists at the cloned muscarinic receptor subtypes, the best correlations were obtained for the m3‐ and m5‐muscarinic receptor subtypes. 5 These data suggest that direct contractile responses of the human detrusor muscle to muscarinic receptor stimulation in vitro are mediated solely via the M₃‐muscarinic receptor subtype with no contribution from the major M₂‐receptor population.     

血清PSA对评估前列腺增生症并急性尿潴留后膀胱尿道功能的意义

目的探讨前列腺增生症（BPH）并急性尿潴留（AUR）后血清前列腺特异抗原（PSA）时评估膀胱尿道功能的临床意义。方法对随机选择的36例已留置尿管的BPH并AUR患者进行尿流动力学检查,且同日行血清PSA测定并分为两组,A组16例（≤8ng/ml）和B组20例（〉8ng／m1）,分析血清PSA与各因素的相关性。结果36例患者血清总PSA（t-PSA）（11．98±6．15）ng/ml,游离PSA（f-PSA）（2．74±0．64）ng/ml,两者均与前列腺体积、膀胱出口梗阻（BOO）、逼尿肌收缩力有相关性（r分别为0．327、0．469,0.272、0．336,0．414、0．419,P值分别为〈0．01、0．01,0．05、0．01,0．01、0．01）,f／tPSA与前列腺体积有相关性（r=0．231,P〈0．05）,而与BOO、逼尿肌收缩力均无相关性。逼尿肌收缩力受损在A组中占81．3％（13／16）,B组中占30％（6／20）。结论对已留置尿管2d以上的BPH并AUR患者,血清PSA高低可间接反映患者逼尿肌收缩力强弱,PSA≤8ng／ml者,其收缩力受损可能性大。     

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

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.     

盆底肌功能锻炼对BPH伴ACD患者术后恢复的影响

目的研究盆底肌功能锻炼对良性前列腺增生（BPH）伴逼尿肌乏力（ACD）患者术后恢复的影响。方法将56例BPH伴ACD患者随机分为观察组和对照组各28例。两组均给予常规护理,观察组加用盆底肌功能锻炼。两组患者均于手术后6个月复查尿动力学及国际前列腺症状评分（IPSS）。结果观察组逼尿肌等容收缩压、最大尿流率均较对照组患者有显著提高（P〈0．05）,而残余尿和IPSS评分则较对照组显著降低（P〈0．01）。结论盆底肌功能锻炼能有效促进BPH伴ACD患者术后膀胱功能的恢复。     

Long-term nitric oxide deficiency causes muscarinic supersensitivity and reduces beta(3)-adrenoceptor-mediated relaxation, causing rat detrusor overactivity

BACKGROUND AND PURPOSE: Overactive bladder is a complex and widely prevalent condition, but little is known about its physiopathology. We have carried out morphological, biochemical and functional assays to investigate the effects of long-term nitric oxide (NO) deficiency on muscarinic receptor and beta-adrenoceptor modulation leading to overactivity of rat detrusor muscle. EXPERIMENTAL APPROACH:Male Wistar rats received N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 7-30 days. Functional responses to muscarinic and beta-adrenoceptor agonists were measured in detrusor smooth muscle (DSM) strips in Krebs-Henseleit solution. Measurements of [(3)H]inositol phosphate, NO synthase (NOS) activity, [(3)H]quinuclidinyl benzilate ([(3)H]QNB) binding and bladder morphology were also performed. KEY RESULTS:Long-term L-NAME treatment significantly increased carbachol-induced DSM contractile responses after 15 and 30 days; relaxing responses to the beta(3)-adrenoceptor agonist BRL 37-344 were significantly reduced at 30 days. Constitutive NOS activity in bladder was reduced by 86% after 7 days and maintained up to 30 days of L-NAME treatment. Carbachol increased sixfold the [(3)H]inositol phosphate in bladder tissue from rats treated with L-NAME. [(3)H]QNB was bound with an apparent K(D) twofold higher in bladder membranes after L-NAME treatment compared with that in control. No morphological alterations in DSM were found. CONCLUSIONS AND IMPLICATIONS:Long-term NO deficiency increased rat DSM contractile responses to a muscarinic agonist, accompanied by significantly enhanced K(D) values for muscarinic receptors and [(3)H]inositol phosphate accumulation in bladder. This supersensitivity for muscarinic agonists along with reductions of beta(3)-adrenoceptor-mediated relaxations indicated that overactive DSM resulted from chronic NO deficiency.     

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)

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.     

Age-dependent contribution of Rho kinase in carbachol-induced contraction of human detrusor smooth muscle in vitro

Aim： Activation of muscarinic receptors on the detrusor smooth muscle is followed by contraction, which involves both myosin light chain kinase （MLCK） and Rho kinase （ROCK）. The aim of this study was to determine the relative contributions of MLCK and ROCK to carbachol-induced contraction of human detrusor smooth muscle in vitro.
Methods： Detrusor smooth muscle strips were prepared from the macroscopically unaffected bladder wall of patients underwent cystectomy. The strips were fixed in an organ bath, and carbachol or KCl-induced isometric contractions were measured by force transducers.

Results： Addition of carbachol （0.4-4 μmol/L） into the bath induced concentration-dependent contractions of detrusor specimens, which was completely abolished by atropine （1 μmol/L）. Pre-incubation of detrusor specimens with either the MLCK inhibitor ML-9 or the ROCK inhibitors HA1100 and Y-27632 （each at 10 μmol/L） significantly blocked carbachol-induced contractions as compared to the time-control experiments. Moreover, MLCK and ROCK inhibition were equally effective in reducing carbachol-induced contractions. The residual carbachol-induced contractions in the presence of both MLCK and ROCK inhibitors were significantly smaller than the contractions obtained when only one enzyme （either MLCK or ROCK） was inhibited, suggesting an additive effect of the two kinases. Interestingly, ROCK-mediated carbachol-induced contractions were positively correlated to the age of patients （r=0.52, P〈0.05）.

Conclusion： Both MLCK and ROCK contribute to carbachol-induced contractions of human detrusor smooth muscle. ROCK inhibitors may be a new pharmacological approach to modulate human bladder hyperactivity.