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Intravesicular resiniferatoxin (RTX) treatment of bladder spasticity

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    Intravesicular resiniferatoxin (RTX) treatment of bladder spasticity

    I just received an enquiry about use of intravesicular capsaicin treatment of bladder spasticity. Earlier, I had posted about this therapy but had not updated people on this topic for a long time. The original work was carried out at the University of Pittsburgh by William DeGroat and his colleagues.

    Several clinical trials had been carried out with capsaicin but it turns out to be inconvenient because capsaicin must be dissolved in alcohol solutions which may be irritating to the bladder. Capsaicin is of course the essence of pepper and the procedure is uncomfortable to those who have feeling in their bladder. Furthermore, the treatment was not uniformly effective in all patients. There have been significant advances in the field since that time. I want to summarize some of these advances.

    A multicenter clinical trial carried out in 2003 used resiniferatoxin (RTX), an analog which is more than 1000x for potent than capsaicin, on 36 patients who have detrusor hyper-reflexivity from spinal cord injury, multiple sclerosis, and other neurological conditions. These patients were refractory to standard anti-spasticity drugs. Use of 1 mM concentrations of RTX was safe produced only modest discomfort (Kim, et al., 2003). Since that time, other clinical trials have shown that the treatment is effective in Taiwan (Kuo, et al., 2006), Portugal (Silva, et al., 2005), Japan (Watanabe, et al. 2004), Italy (Lazzeri, et al., 2004), Switzerland (Reitz & Schurch, 2004), and France (de Seze, et al., 2004).

    However, the treatment is effective in only about a third of patients with neurogenic bladder spasticity (Kuo, et al., 2005; Kuo, 2003; Palma, et al. 2004). Shin, et al. (2006) reported that the effectiveness of intravesical RTX depended on the presence of unmyelinated C fibers which can be tested by ice provocative urodynamic studies. The treatment was not effective for patients with interstitial cystitis (Chen, et al. 2005; Payne, et al., 2005). Giannantoni, et al., (2004) reported that botox therapy is more effective than intravesical RTX.

    So, in summary, RTX therapy is now preferred over capsaicin and, because it is not effective in all patients, it should be carried out in selected patients who show responses to ice-provocation urodynamic tests. Some doctors prefer to use botox but both the safety and absence of side effects of RTX therapy argue in its favor.

    References Cited
    • de Groat WC and Yoshimura N (2006). Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury. Prog Brain Res 152: 59-84. The lower urinary tract has two main functions, the storage and periodic expulsion of urine, which are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the pelvic floor). During urine storage the outlet is closed and the bladder is quiescent, thereby maintaining a low intravesical pressure over a wide range of bladder volumes. During micturition the outlet relaxes and the bladder contracts to promote the release of urine. This reciprocal relationship between bladder and outlet is generated by visceral reflex circuits, some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are presumably involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter functions. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. Studies in animals indicate that the recovery of bladder function after spinal cord injury is dependent in part on plasticity of bladder afferent pathways and the unmasking of reflexes triggered by capsaicin-sensitive C-fiber bladder afferent neurons. The plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons, and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs. Department of Pharmacology and Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    • Kim JH, Rivas DA, Shenot PJ, Green B, Kennelly M, Erickson JR, O'Leary M, Yoshimura N and Chancellor MB (2003). Intravesical resiniferatoxin for refractory detrusor hyperreflexia: a multicenter, blinded, randomized, placebo-controlled trial. J Spinal Cord Med 26: 358-63. OBJECTIVE: Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH). METHODS: Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 mL of placebo (n = 8 patients) or 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, or 1.0 microM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 12 posttreatment. RESULTS: Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Patients in the 0.5-microM and 1.0-microM groups with MCC < 300 mL at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. There were no long-term complications. CONCLUSION: Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy. Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
    • Kuo HC, Liu HT and Yang WC (2006). Therapeutic effect of multiple resiniferatoxin intravesical instillations in patients with refractory detrusor overactivity: a randomized, double-blind, placebo controlled study. J Urol 176: 641-5. PURPOSE: Previous study has shown that multiple intravesical instillations of resiniferatoxin (Sigma) at 10 nM has therapeutic effects in patients with detrusor overactivity. To our knowledge the placebo effect of multiple instillations of low dose resiniferatoxin for neurogenic and nonneurogenic detrusor overactivity has not been investigated. In this randomized, double-blind, placebo controlled study we evaluated the therapeutic effects of this resiniferatoxin treatment. MATERIALS AND METHODS: A total of 54 patients with detrusor overactivity refractory to anticholinergics were enrolled and randomly treated with 4 weekly intravesical instillations of 10 nM resiniferatoxin (26) or vehicle, consisting of 10% ethanol in normal saline, as the control group (28). The clinical effects of treatment on incontinence grade, incontinence episodes, general satisfaction, lower urinary tract symptoms and urodynamic parameters were assessed. RESULTS: Three months after completing the 4 intravesical treatments the resiniferatoxin treatment group had a significantly higher percent of patients with excellent and improved results compared to the control group (19.2% vs 7.1% and 42.3% vs 14.2%, respectively, each p < 0.001). Treatment remained effective at 6 months in 13 patients (50%) in the resiniferatoxin group but in only 3 (11%) in the control group (p < 0.001). Bladder capacity was significantly increased and symptom scores significantly improved 3 months after treatment in the resiniferatoxin group but not in the control group. CONCLUSIONS: Multiple intravesical instillations of 10 nM resiniferatoxin were effective for improving the incontinence grade in 62% of patients at 3 months, of whom 50% maintained a therapeutic effect 6 months after treatment. The therapeutic effect of resiniferatoxin was significantly superior to that of placebo. Department of Urology, Buddhist Tzu Chi General Hospital and Buddhist Tzu Chi University School of Medicine, Hualien, Taiwan, Republic of China.
    • Silva C, Silva J, Ribeiro MJ, Avelino A and Cruz F (2005). Urodynamic effect of intravesical resiniferatoxin in patients with neurogenic detrusor overactivity of spinal origin: results of a double-blind randomized placebo-controlled trial. Eur Urol 48: 650-5. OBJECTIVES: To access by a placebo-controlled randomized clinical trial the effect of intravesical resiniferatoxin on the urodynamic parameters of patients with neurogenic detrusor overactivity (NDO) of spinal origin. METHODS: Twenty eight patients with spinal NDO were randomised to receive intravesically 50 nM resiniferatoxin dissolved in 10% ethanol in saline (RTX group) or only the vehicle solution (placebo group). Filling cystometries were obtained in each patient at 1 month and 1 week before and at 1 and 3 months after treatment. In a visual analog scale patients were asked to estimate the discomfort induced by treatment. Patients were also persuaded to fill a micturition chart during the 3 days preceding each cystometry. RESULTS: The RTX and placebo groups were homogeneous in what respects the volume to first involuntary detrusor contraction (FDC, 143+/-95 ml and 115+/-58 ml, respectively, p=0.3) and maximal cystometric capacity (MCC, 189+/-99 ml and 198+/-111 ml, respectively, p=0.8). At the end of the study, mean FDC and MCC in the RTX group, 184+/-93 ml and 314+/-135 ml, respectively were significantly higher than in the placebo group, 115+/-61 ml (p=0.03) and 204+/-92 ml (p=0.02). In the visual analogue scale discomfort caused by treatment was similar. Only 10 patients in the RTX group and 6 patients in the placebo group completed adequately the micturition chart. Mean frequency and urinary incontinence decreased significantly only in the RTX group. CONCLUSIONS: Intravesical RTX is effective in increasing bladder capacity in spinal NDO patients. Such increment might contribute to decrease urinary frequency and incontinence of these patients. Department of Urology, Hospital S. Joao, 4200-319 Porto, Portugal.
    • Watanabe T, Yokoyama T, Sasaki K, Nozaki K, Ozawa H and Kumon H (2004). Intravesical resiniferatoxin for patients with neurogenic detrusor overactivity. Int J Urol 11: 200-5. BACKGROUND: Resiniferatoxin (RTX), a substance isolated from some species of Euphobia, is a specific C-fiber neurotoxin which produces desensitization rather than excitation. At first, we performed intravesical RTX therapy on eight patients with neurogenic detrusor overactivity. After we confirmed the safety and efficacy, a Japanese RTX study group was organized and a new protocol made. The multicenter trial was performed in Japan. However, the efficacy of the treatments was different among the institutions. Therefore, we have compared the results between the first protocol and the new one at our hospital. METHODS: The first and second protocol involved the RTX solution (30 mL of 500 nM, and 100 mL of 1 micro M, respectively) being instillated in the bladder for 30 min by almost the same procedures. Effects on bladder function were evaluated during treatment and at follow up. RESULTS: For the first and second protocols, six out of eight patients noted symptomatic improvement while two patients did not notice any change in the degree of incontinence for one month. The mean urodynamic bladder capacity had significantly increased from 138.0 +/- 64.4 mL to 227.3 +/- 112.4 mL and 133.1 +/- 43.3 mL to 247.0 +/- 102.3 mL 1 month after RTX treatment for the first and second protocols, respectively (P < 0.05). No severe side-effects were seen in either group. CONCLUSION: Intravesical RTX improved bladder capacity in patients with neurogenic detrusor overactivity in both protocols. The concentration of RTX did not exhibit any change in the effect and safety in our hospital. Intravesical RTX is a promising treatment for neurogenic detrusor overactivity. Department of Urology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
    • Lazzeri M, Spinelli M, Zanollo A and Turini D (2004). Intravesical vanilloids and neurogenic incontinence: ten years experience. Urol Int 72: 145-9. INTRODUCTION: In this study we critically review our '10-year' experience with intravesical vanilloids (capsaicin and resiniferatoxin) in the treatment of neurogenic incontinence, addressing the issue of their introduction into daily clinical practice. MATERIALS AND METHODS: From July 1992 to June 2001, 54 patients suffering from detrusor hyperreflexia, due to spinal cord injuries, received intravesical instillation of capsaicin, and from January 1995 to June 2001, 47 patients received intravesical instillation of resiniferatoxin (RTX) in order to treat bladder dysfunction and symptoms. All patients presented detrusor hyperreflexia refractory to oral and/or intravesical oxibutynin and they displayed high-voiding pressure associated with frequent urine leakage. Capsaicin was used at a concentration of 10 mM; RTX was tested in two different concentrations: 10 nM and 10 microM. The outcome was considered according to simple parameters: (i) the number of patients who reported an improvement in clinical status (patient dry between clean intermittent catheterization) and urodynamic status (a bladder capacity 50% higher than pretreatment capacity, lasting more than 3 months after the instillation); (ii) the number of patients who continued intravesical therapy; (iii) the number of instillations they received; (iv) the length of the interval between 2 consecutive instillations, and (v) alternative therapies when vanilloids failed. RESULTS: The topical intravesical instillation of capsaicin produced an improvement in symptoms and urodynamic parameters, in 29 patients (53.7%) after 3 months. In these 29 patients only 7 (24.13%) continued to received capsaicin in June 2001. The mean follow-up was 32.28 +/- 14.20 (range 8-52) months, the mean number of instillations was 6.14 +/- 2.54 (range 2-10) and the mean interval between the 2 consecutive instillations was 7.14 +/- 2.60 (range 4-12) months. The topical intravesical instillation of RTX produced an improvement in symptoms and urodynamic parameters in 73.33% of patients (a total of 45 patients) who received 10 microM. 18 of them (54.54%) continued to received RTX in June 2001. The mean follow-up was 27.88 +/- 10.95 (range 11-49) months, the mean number of instillations was 4.33 +/- 1.60 (range 2-8). The mean interval between 2 consecutive instillations was 9.61 +/- 2.99 (ranged 4-16) months. CONCLUSION: The results obtained using RTX seem to be very promising with regard to efficacy and tolerance, particularly in comparison with capsaicin. Even if the number of patients who received capsaicin and RTX remains small, the intravesical vanilloid receptor agonist RTX could offer an attractive alternative to oral medications in the treatment of neurogenic incontinence. Department of Urology, 'Casa di Cura Santa Chiara Firenze', Florence, Italy.
    • Kuo HC (2005). Multiple intravesical instillation of low-dose resiniferatoxin is effective in the treatment of detrusor overactivity refractory to anticholinergics. BJU Int 95: 1023-7. OBJECTIVE: To examine the effectiveness and tolerability of multiple intravesical instillations of 10 nmol/L resiniferatoxin in patients with detrusor overactivity (DO) refractory to anticholinergic agents, as not all these patients are successfully treated by one such instillation. PATIENTS AND METHODS: The study included 53 patients with DO from neurogenic (NDO, 10), previous bladder outlet obstruction (BOO, 20) or idiopathic cause (IDO, 23) and who were refractory to anticholinergic agents. Patients received three to four instillations of 10 nmol/L resiniferatoxin, as outpatients. The International Prostate Symptom Score and quality-of-life index were recorded, and a video-urodynamic study conducted at baseline and 3 months after treatment. The therapeutic results and urodynamic variables were compared among patients with different causes of DO. RESULTS: Four patients withdrew from the study after the first instillation because of urinary tract infection or severe pain on urination, leaving 49 who completed at least three instillations. The overall results were an excellent response in 17 patients (35%), improvement in 13 (27%) and failure in 19 (39%); the treatment was deemed a success (excellent or improved) in 16 of 20 with previous BOO, 11 of 19 with IDO, and only three of 10 with NDO (P = 0.011). Patients had significant improvements in the storage symptom score, total symptom score and quality-of-life index after treatment. The cystometric capacity and the postvoid residual were significantly greater and voiding efficiency significantly less after treatment. DO during the urodynamic study was absent in 12 patients after treatment. CONCLUSIONS: Multiple intravesical instillations of 10 nmol/L resiniferatoxin are effective in treating patients with DO refractory to anticholinergics. Department of Urology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
    • Kuo HC (2003). Effectiveness of intravesical resiniferatoxin for anticholinergic treatment refractory detrusor overactivity due to nonspinal cord lesions. J Urol 170: 835-9. PURPOSE: Evidence suggests that unmyelinated C fibers become predominant in the mediation of the detrusor reflex in patients with chronic spinal cord lesions and possibly in idiopathic detrusor hyperactivity. Intravesical vanilloid therapy might be effective in treating refractory detrusor overactivity due to nonspinal cord lesion. This study investigated the clinical effect of intravesical resiniferatoxin in treating detrusor overactivity of nonspinal cord lesions refractory to anticholinergics. MATERIALS AND METHODS: A total of 41 patients received intravesical resiniferatoxin therapy with 10 ml of 100 nM resiniferatoxin in 10% ethanol solution for 40 minutes. The clinical effects on a decrease in incontinence episodes and urodynamic study were evaluated at baseline and after treatment. Clinical improvement was considered if patients became dry or had a decrease in incontinence episodes of 50%. Therapeutic results were analyzed by disease category and type of initial detrusor response. RESULTS: Of the 41 patients 10 had neurogenic lesions, 18 had previous transurethral prostatectomy and 13 had idiopathic detrusor overactivity. There were 20 women and 21 men with a mean age of 73.6 years (range 43 to 82) and a symptom duration of 3.6 +/- 4.5 years. After resiniferatoxin treatment 21 patients had clinical improvement (51.2%) including 5 with neurogenic (50%), 11 with previous transurethral prostatectomy (61.1%) and 5 with idiopathic detrusor overactivity (38.5%). An improvement was found in 11 patients with type I initial response (84.6%), 3 patients with type II response (23%) and 7 patients with type III response (46.7%). The 21 patients with improvement had a significant increase in cystometric capacity (208 +/- 80.7 vs 287.2 +/- 118.6 ml, p = 0.001) and a significant decrease in detrusor pressure (33.6 +/- 11.1 vs 27.4 +/- 11.8 cmH(2)O, p = 0.047), but no significant difference in maximal flow rate and residual urine volume. CONCLUSIONS: Intravesical resiniferatoxin was effective in treating refractory detrusor overactivity in 51.2% of patients with nonspinal cord lesions. Patients with detrusor overactivity due to previous bladder outlet obstruction benefited the most. Detrusor contractility decreased after resiniferatoxin treatment in the group with improvement but did not influence voiding efficiency. The initial detrusor response to resiniferatoxin treatment might predict the clinical outcome. Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3 Chung Yang Road, Hualien, Taiwan.
    • Reitz A and Schurch B (2004). Intravesical therapy options for neurogenic detrusor overactivity. Spinal Cord 42: 267-72. STUDY DESIGN: Review article. SETTING: Neuro-Urology, Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland. OBJECTIVES: This review considers intravesical treatment options of neurogenic detrusor overactivity and discusses the underlying mechanism of action, clinical safety and efficacy, and the future trends. METHODS: The available literature was reviewed using medline services. RESULTS: Oral anticholinergic drugs are widely used to treat detrusor overactivity, but they are ineffective in some patients or cause systemic side effects such as blurred vision or dry mouth. As an alternative, topical therapy strategies have been suggested to achieve a profound inhibition of the overactive detrusor and to avoid high systemic drug levels. Currently available intravesical treatment options either act on the afferent arc of the reflex such as local anaesthetics or vanilloids or on the efferent cholinergic transmission to the detrusor muscle such as intravesical oxybutynin or botulinum toxin. Although an established and effective therapy, intravesical oxybutynin is not widely used. Evidence for clinical significance of intravesical atropine and local anaesthetic is missing. Intravesical capsaicin has been shown to improve clinical and urodynamic parameters, but cause pain in some patients. The intravesical instillation of resiniferatoxin and the injection of botulinum-A toxin into the detrusor muscle are promising new options; however, randomised placebo-controlled studies to prove their safety and efficacy are still missing. CONCLUSION: Intravesical treatment strategies in patients with neurogenic detrusor overactivity may provide alternatives to established therapies such as oral anticholinergics. The selectivity of the intravesical treatment and the reduction or even the absence of side effects are major advantages of this topical approach. Neuro-Urology, Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland.
    • de Seze M, Wiart L, de Seze MP, Soyeur L, Dosque JP, Blajezewski S, Moore N, Brochet B, Mazaux JM, Barat M and Joseph PA (2004). Intravesical capsaicin versus resiniferatoxin for the treatment of detrusor hyperreflexia in spinal cord injured patients: a double-blind, randomized, controlled study. J Urol 171: 251-5. PURPOSE: Chemical defunctionalization of C-fiber bladder afferents with intravesical vanilloids such as capsaicin (CAP) or resiniferatoxin (RTX) improves detrusor hyperreflexia in humans and animals. The little existing data comparing the efficacy and tolerance of these 2 vanilloid agents seem to favor RTX in 10% alcohol over CAP, which is usually diluted in 30% alcohol. We compared the efficacy and tolerability of the 2 vanilloid agonists in what to our knowledge is the first randomized, controlled study comparing nonalcohol CAP vs RTX in 10% alcohol in neurogenic patients with detrusor hyperreflexia. MATERIALS AND METHODS: This single center, randomized, double-blind, parallel groups study included 39 spinal cord injured adults with detrusor hyperreflexia. On day 0 patients were randomized to receive 1, 100 ml intravesical instillation of 100 nMol/l RTX diluted in 10% ethanol or 1 mmol/l CAP diluted in glucidic solvent. Efficacy (voiding chart and cystomanometry) and tolerability were evaluated during a 3-month followup. RESULTS: On day 30 clinical and urodynamical improvement was found in 78% and 83% of patients with CAP vs 80% and 60% with RTX, respectively, without a significant difference between the 2 treated groups. The benefit remained in two-thirds of the 2 groups on day 90. There were no significant differences in regard to the incidence, nature or duration of side effects in CAP vs RTX treated patients. CONCLUSIONS: Our results strongly argue for the importance of accounting for the role of vanilloid solute when interpreting the efficacy and tolerance of vesical vanilloid instillation in detrusor hyperreflexia cases. They suggest that a glucidic solute is a valuable solvent for vanilloid instillation. Department ofPhysical Medicine and Rehabilitation, Bordeaux University Hospital, France.
    • Chen TY, Corcos J, Camel M, Ponsot Y and Tu le M (2005). Prospective, randomized, double-blind study of safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC). Int Urogynecol J Pelvic Floor Dysfunct 16: 293-7. OBJECTIVE: To determine the safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC) patients. MATERIALS AND METHODS: IC patients were instilled with 50 cc of test solution containing either placebo, 0.05 microM or 0.10 microM RTX in the bladder. Plasma concentration of RTX and its degradant resiniferonol 9-, 13-, 14-orthophenylacetate was measured. Immediate post-treatment blood sampling and cystoscopy were performed. Symptoms were evaluated before treatment, at 4- and at 12-week follow-ups, using VAS indicator for pain, voiding diary, and O'Leary's IC symptom/problem indices. RESULTS: Among 22 patients observed (ten in 0.10 microM RTX, eight in 0.05 microM RTX, and four in placebo groups), the most commonly reported adverse event was pain during instillation (80.0%, 87.5%, and 25.0%). No serious adverse events were reported. CONCLUSIONS: Use of intravesical RTX in IC patients is associated with important tolerability issues but safe at 0.10 microM and 0.05 microM. Centre Hospitalier Universitaire de Sherbrooke, Service d'urologie 3001, Canada.
    • Payne CK, Mosbaugh PG, Forrest JB, Evans RJ, Whitmore KE, Antoci JP, Perez-Marrero R, Jacoby K, Diokno AC, O'Reilly KJ, Griebling TL, Vasavada SP, Yu AS and Frumkin LR (2005). Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol 173: 1590-4. PURPOSE: Interstitial cystitis is a painful bladder condition of unknown etiology and poorly understood pathophysiology. Current therapies have met with limited success. Vanilloid receptor agonists such as resiniferatoxin (RTX) desensitize C-fibers that transmit pain; it is hypothesized that such drugs will be effective in the treatment of interstitial cystitis and painful bladder syndrome by decreasing the pain that leads to urinary frequency and urgency. MATERIALS AND METHODS: A randomized, double-blind, placebo controlled study was conducted in 163 patients with interstitial cystitis. Participants were randomly assigned to receive a single intravesical dose of 50 ml of either RTX 0.01 microM, 0.05 microM, 0.10 microM, or placebo. Safety and efficacy was evaluated over 12 weeks. The primary efficacy endpoint was the Global Response Assessment, a 7-point scale rating overall change in symptoms of interstitial cystitis after 4 weeks. Secondary efficacy endpoints included reduction in pain, urgency, frequency, nocturia, average void volume, and the O'Leary-Sant Symptom and Problem Indexes. RESULTS: RTX did not improve overall symptoms, pain, urgency, frequency, nocturia, or average void volume during 12 weeks followup. RTX resulted in a dose-dependent increase in the incidence of instillation pain, but was otherwise generally well tolerated. CONCLUSIONS: In the largest prospective, randomized clinical trial reported to date with intravesical vanilloid therapy, single administration of RTX at doses of 0.01 microM to 0.10 microM was not effective in patients with interstitial cystitis. Stanford University School of Medicine, Stanford, California, USA.
    • Palma PC, Thiel M, Riccetto CL, Dambros M, Miyaoka R and Netto NR, Jr. (2004). Resiniferatoxin for detrusor instability refractory to anticholinergics. Int Braz J Urol 30: 53-8. PURPOSE: We have evaluated the clinical and urodynamic effects of intravesical instillation of resiniferatoxin in patients with idiopathic detrusor instability refractory to anticholinergics. MATERIALS AND METHODS: There were 30 women, median age 56 years old with detrusor instability for over 6 months and a history of anticholinergic use with no response or intolerable collateral effects. A 50 nM solution of resiniferatoxin was prepared for intravesical instillation. All patients were evaluated for urinary symptoms, as well as for urodynamic assessments before and 30 days after instillation. Tolerability was analyzed during the instillation. RESULTS: A clinical improvement was observed in 30% of the patients with urinary urgency and in 33% of the patients with urge-incontinence. The mean maximum cystometric capacity before application was 303.9 +/- 78.9 and after application 341 +/- 84.6. No significant difference was observed (p = 0.585). The mean maximum amplitude of the contractions diminished from 47.86 +/- 29.64 to 38.72 +/- 30.77 (p = 0.002). CONCLUSIONS: Resiniferatoxin, in this concentration, proved to be useful in a small percentage of patients regarding clinical detrusor instability. Maximum amplitude of the involuntary contractions was significantly reduced and in 33% patients the involuntary contractions disappeared. Further studies with different concentrations are recommended. Division of Urology, State University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil.
    • Shin JC, Kim YW, Park CI, Kang SW and Yang SC (2006). Effect of the intravesical resiniferatoxin instillation evaluated by the ice provocative urodynamic study. Spinal Cord 44: 309-14. STUDY DESIGN: Prospective urodynamic investigation before and after intravesical resiniferatoxin instillation treatment. OBJECTIVE: To evaluate the effectiveness of intravesical resiniferatoxin instillation for the treatment of neurogenic detrusor overactivity (NDO), using conventional and ice provocative urodynamic studies to monitor the activity of the unmyelinated C-fiber. SETTING: Spinal Cord Injury Unit, Yonsei Rehabilitation Hospital, Seoul, Korea. METHODS: A measure of 100 ml of resiniferatoxin solution, at a concentration of 100 nM diluted in 10% ethanol, was intravesically instilled into the bladder of 15 spinal cord injury patients with NDO. Conventional and ice provocative urodynamic studies were performed to evaluate the change in the involuntary detrusor activity, reflex volume, maximal bladder capacity, compliance, maximal detrusor pressure and reflex volume ratio 7 days before and 30 days after the instillation. RESULTS: Before the intravesical resiniferatoxin instillation, all patients exhibited NDO in both the conventional and ice provocative urodynamic studies, with a mean reflex volume ratio of 0.45+/-0.22. There was no significant change in the maximal bladder capacity, compliance and maximal detrusor pressure at the follow-up urodynamic study, but the reflex volume ratio was significantly increased (P<0.05) after the intravesical resiniferatoxin instillation. Among the 15 patients, three (20%) showed complete and nine (60%) partial suppression of the unmyelinated C-fiber activities. CONCLUSION: Intravesical resiniferatoxin instillation was partially controlled by the unmyelinated C-fiber activities, which were estimated by an ice provocative urodynamic study. Therefore, further studies on the optimal dosage and accurate indications for resiniferatoxin instillation are required. Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.
    • Giannantoni A, Di Stasi SM, Stephen RL, Bini V, Costantini E and Porena M (2004). Intravesical resiniferatoxin versus botulinum-A toxin injections for neurogenic detrusor overactivity: a prospective randomized study. J Urol 172: 240-3. PURPOSE: We investigated the effectiveness and safety of intravesical resiniferatoxin (Sigma Chemical Co., St. Louis, Missouri) and botulinum-A toxin injections into the detrusor muscle in a group of spinal cord injured patients with neurogenic detrusor overactivity unresponsive to conventional anticholinergic therapy. MATERIALS AND METHODS: A total of 25 patients were randomly assigned to receive intravesically 0.6 microM resiniferatoxin in 50 ml of 0.9% NaCl or injections into the detrusor muscle of 300 units botulinum A-toxin diluted in 30 ml 0.9% NaCl. Clinical evaluation and urodynamics were performed at baseline, and at 6, 12 and 18 months after treatment. RESULTS: In both arms there was a significant decrease in catheterization and incontinent episodes, and a significant increase in first detrusor contraction and maximum bladder capacity at 6, 12 and 18-month followup. There were no local side effects with either treatment. Botulinum-A toxin induced a significant decrease in the frequency of daily incontinence episodes (p <0.05), a significant increase in first uninhibited detrusor contraction (p <0.01) in maximum bladder capacity (p <0.01), and a significant decrease in maximum pressure of uninhibited detrusor contractions (p <0.01) compared to resiniferatoxin at 6, 12 and 18-month followup. CONCLUSIONS: In spinal cord injured patients with refractory neurogenic detrusor overactivity, intravesical resiniferatoxin and botulinum-A toxin injections into the detrusor muscle provided beneficial clinical and urodynamic results with decreases in detrusor overactivity and restoration of urinary continence in a large proportion of patients. Botulinum-A toxin injections provided superior clinical and urodynamic benefits compared to those of intravesical resiniferatoxin. Department of Urology, University of Perugia, Perugia, Italy.