resiniferatoxin and Urinary-Bladder--Neurogenic

The bladder is an organ rich in vanilloid targets: dense unmyelinated c-fibers partially responsible for bladder sensation and response to noxious stimuli. Drugs such as capsaicin and resiniferatoxin (RTX) interact with the VR1 vanilloid receptor subtype to initially excite then subsequently desensitize the c-fibers. This chapter examines the literature describing the use of vanilloid receptor agonists in the treatment of the following urological disorders: neurogenic bladder (NGB), overactive bladder (OAB), and interstitial cystitis/painful bladder syndrome (IC/PBS). Review of the literature was performed using Pubmed and the following key words "capsaicin," "resiniferatoxin (RTX)," and "neurogenic bladder," "overactive bladder (OAB)," and "interstitial cystitis," "painful bladder syndrome." Articles focusing on randomized trials comparing intravesical administration of a vanilloid receptor agonist to placebo and those in English were reviewed. We conclude that capsaicin and RTX do appear to provide some acceptable treatment results in patients with neurogenic bladder, though larger studies are needed to confirm this. Although efficacy has been shown in some studies, currently the use of vanilloids cannot be recommended for routine use in patients with OAB as the need for catheterization may cause the risk to outweigh the benefit of treatment. Similarly, for the treatment of BPS, vanilloid receptor agonists lack strong evidence for efficacy or tolerability; larger studies are needed to define their role. Understanding how vanilloids are able to impact these disorders, however, may help further elucidate their underlying pathophysiological processes.

Topics: Capsaicin; Cystitis, Interstitial; Diterpenes; Humans; Urinary Bladder, Neurogenic; Urinary Bladder, Overactive

In the first part of this review the potential pathophysiological factors involved in the overactive bladder were outlined, and the wide range of first-line anticholinergic pharmacotherapies available for such patients were reviewed. The second part will focus on the intravesical instillation of resiniferatoxin and injections of botulinum toxin into the bladder to treat overactive bladder and detrusor overactivity. Resiniferatoxin has been shown to increase bladder capacity and improve incontinence in patients with neurogenic and non-neurogenic detrusor overactivity. Botulinum toxin has successfully been used to treat neurogenic and idiopathic detrusor overactivity, with improvements observed in bladder capacity, decreases in detrusor pressures on filling and voiding, and increased volumes at first contraction. Further validation is required for both treatments, in the form of large randomised controlled trials, before their use can be considered routine, with particular focus on dosing required.

Topics: Administration, Intravesical; Botulinum Toxins; Cholinergic Antagonists; Diterpenes; Dose-Response Relationship, Drug; Drugs, Investigational; Humans; Neurotoxins; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Treatment Failure; Urinary Bladder, Neurogenic; Urinary Incontinence

Patients with neurogenic bladder represent a small fraction of the total overactive bladder population. As a consequence, development of new therapies in this area has largely focused on idiopathic urinary incontinence. The absence of data for patients with neurological disease has far-reaching implications, affecting reimbursement and physicians' willingness to prescribe therapies, and limiting access of potential valuable treatments to patients whose lives are significantly impaired by inadequately managed bladder symptoms.. The range of new therapies is increasing. Although many reviews of the overall safety, efficacy and mode of action of such treatments are available, there is limited information on how these treatments will best be used in clinical practice. We considered the current benefits and limitations of the various new licensed and unlicensed therapies and what role each would have in the future management of neurogenic urinary incontinence.. A wide range of new treatments have been investigated for the management of overactive bladder; few, however, have been evaluated extensively in neurogenic urinary incontinence. Further studies are required to determine the optimal dosing regimes and formulations for individual sub-populations of neurogenic bladder patients and to determine the cost-effectiveness of these interventions. With the current experience available, two treatment algorithms for a subset of patients with neurological disease have also been proposed, which suggest at which stage of management and in which patients individual therapies for neurogenic urinary incontinence could be used.

Topics: Algorithms; Botulinum Toxins, Type A; Cannabinoids; Capsaicin; Cholinergic Antagonists; Diterpenes; Humans; Muscarinic Antagonists; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence

In recent years, important improvements in the management of patients with neurogenic or non-neurogenic detrusor overactivity and urge incontinence have been brought about by the introduction of vanilloids and botulinum toxins in urology. In this review we introduce the new therapeutic options, provides basic information, and summarize the results experienced so far.

Topics: Botulinum Toxins; Capsaicin; Diterpenes; Female; Humans; Neurotoxins; Pelvic Floor; Treatment Outcome; Urinary Bladder; Urinary Bladder, Neurogenic; Urinary Incontinence

Refractory neurogenic detrusor overactivity refers to the clinical condition that is no longer manageable by anticholinergic therapy. This condition represents a formidable task to caregivers because the treatment of urinary incontinence and adequate protection of the upper urinary tract become extremely difficult. Treatment options for refractory neurogenic detrusor overactivity include detrusor injections of botulinum toxin and intravesical instillation of vanilloid compounds, mainly resiniferatoxin, or anticholinergic drugs. If these options fail, bladder augmentation or sacral anterior root stimulation offers excellent outcomes, although at much higher costs and risks to the patients.

Topics: Botulinum Toxins, Type A; Cholinergic Antagonists; Diterpenes; Humans; Neuromuscular Agents; Neurotoxins; Treatment Failure; Urinary Bladder, Neurogenic; Urinary Bladder, Overactive

Review article.. Neuro-Urology, Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland.. 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.. The available literature was reviewed using medline services.. 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.. 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.

Topics: Administration, Intravesical; Botulinum Toxins, Type A; Cholinergic Antagonists; Diterpenes; Humans; Muscle Hypertonia; Muscle, Smooth; Treatment Outcome; Urinary Bladder; Urinary Bladder, Neurogenic

It is estimated that almost 70% of patients affected by multiple sclerosis (MS) suffer from urinary symptoms, with devastant impact on Quality of Life (QoL). The major aims of management should be to ameliorate the patients quality of life and to prevent the frequent complications of bladder dysfunction such as infention and renal damage. Therapy can usually eliminate or reduce the symptoms of neuropathic bladder. In the following pages is discussed the complex management of urinary symptoms in MS patients.

Topics: Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Botulinum Toxins; Capsaicin; Cresols; Diterpenes; Electric Stimulation Therapy; Humans; Multiple Sclerosis; Muscarinic Antagonists; Phenylpropanolamine; Prognosis; Quality of Life; Time Factors; Tolterodine Tartrate; Urinary Bladder, Neurogenic; Urodynamics

Detrusor overactivity is a relatively common yet embarrassing symptom complex with significant impact on quality of life. The mainstay of current pharmacological treatment involves use of muscarinic receptor antagonists, but their therapeutic efficacy is limited by their troublesome side effects resulting in the non-continuance of treatment in a significant number of patients. Therefore, the development of new drugs can proceed by targeting alternative pathways affecting detrusor overactivity. In this article, the pharmacological basis for the current therapeutic alternatives for managing detrusor overactivity and possible future developments are discussed.. It is clear that far from being a passive container for urine, the urothelium is a crucial part of the bladder. Its functions are complex, dynamic and important, and only now becoming understood. The release of ATP from urothelium in response to distension and its action on P2X receptors resulting in activating both motor and sensory neurons is being increasingly recognised. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction. However, in functionally abnormal bladders, a non-cholinergic activation via the purinergic receptors may occur. The central nervous mechanisms controlling the micturition reflex have also recently attracted attention.. Recent research has suggested that several transmitters may modulate voiding. However, few drugs with clinical benefits have been developed so far. Present treatments for overactive bladders have significant non-compliance rates. Hopefully, future research will lead to drugs with greater therapeutic benefits and better tolerance.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Botulinum Toxins, Type A; Capsaicin; Diterpenes; Female; Humans; Muscarinic Antagonists; Potassium Channels; Tachykinins; Urinary Bladder; Urinary Bladder, Neurogenic; Urination

Topics: Administration, Intravesical; Animals; Capsaicin; Diterpenes; Humans; Urinary Bladder, Neurogenic; Urinary Incontinence

A few decades ago, urinary diversion, usually with an ileal conduit, was the ultimate outcome for most children with spina bifida. The revolutionary institution of clean intermittent catheterization has changed the algorithm totally. Furthermore many new drugs have been developed during the past decade and have decreased the need for surgery dramatically. In this article, we will focus on the most recent data on new modalities of therapy to help avoid urinary diversion or bladder augmentation.. In addition to clean intermittent catheterization and oxybutynin treatment, a new generation of anticholinergic medications, such as tolterodine, has been developed. For patients who drop out because of the side-effects of oral administration, new methods of administration are now available, including extended release and intravesical instillation. For those unresponsive, botulinum-A toxin and resiniferatoxin are two relatively new drugs in the field, administered as intravesical injection and instillation, respectively. Intravesical or transdermal electrical stimulation, sacral nerve stimulation and biofeedback therapy are under development, but as currently administered, are not yet completely successful.. Although life-saving in many respects, bladder augmentation introduces life-long risks of its own. Our goal in describing 'conservative' management is to prevent this step. Many alternatives to surgery are available now and more effective strategies are under development.

Topics: Anti-Dyskinesia Agents; Benzhydryl Compounds; Biofeedback, Psychology; Botulinum Toxins; Child; Child, Preschool; Cholinergic Antagonists; Cresols; Diterpenes; Electric Stimulation Therapy; Humans; Infant; Infant, Newborn; Mandelic Acids; Meningomyelocele; Muscarinic Antagonists; Phenylpropanolamine; Tolterodine Tartrate; Urinary Bladder, Neurogenic; Urinary Catheterization

Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.

Topics: Administration, Intravesical; Animals; Capsaicin; Diterpenes; Female; Humans; Nerve Fibers; Neurotoxins; Urinary Bladder; Urinary Bladder, Neurogenic; Urinary Incontinence

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.. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Aged; Diterpenes; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscle Contraction; Muscle Hypertonia; Pain Measurement; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence; Urodynamics

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.. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Capsaicin; Diterpenes; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurotoxins; Reflex, Abnormal; Spinal Cord Injuries; Urinary Bladder, Neurogenic

To investigate endothelial nitric oxide synthase (eNOS) immunoreactivity in bladder biopsies from patients with neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, and compare this with control material; the distribution of two other vascular markers, von Willebrand Factor (vWF) and the vascular endothelial growth factor (VEGF), was also studied.. Flexible cystoscopic bladder biopsies from eight controls investigated for asymptomatic microhaematuria and 19 patients with refractory spinal NDO enrolled in a clinical trial of intravesical treatment with escalating doses of resiniferatoxin were immunostained with polyclonal rabbit antibodies for eNOS, vWF and VEGF. Fewer baseline NDO specimens (eight) were available for vWF and VEGF staining. Computerized image analysis was used to quantify immunoreactivity, and the Mann-Whitney test for statistical analysis.. eNOS immunoreactivity was found in the suburothelium and less often in the urothelium, with a distribution indicating a location in small blood vessels at the urothelium-suburothelium junction. Immunostaining for vWF showed a similar location. There was a trend to higher eNOS values before treatment in those responding than in those not responding to resiniferatoxin (P = 0.059), and a significant reduction in eNOS immunoreactivity after successful treatment (P = 0.016). VEGF staining was weaker but there was a significant increase in pretreatment biopsies of responders to resiniferatoxin (P = 0.048). Clinical and histopathology features were similar in both groups.. The trend for higher eNOS expression in patients with NDO who responded to resiniferatoxin suggests that increased vasculature or vasodilatation in the suburothelium may be necessary for successful intravesical treatment. Further studies with more patients are required to confirm this relationship and to examine the mechanisms underlying changes in vasculature with levels of bladder overactivity.

Topics: Administration, Intravesical; Biopsy; Diterpenes; Double-Blind Method; Humans; Immunohistochemistry; Middle Aged; Neurotoxins; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Prospective Studies; Urinary Bladder; Urinary Bladder, Neurogenic; Vascular Endothelial Growth Factor A

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.. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Clinical Protocols; Diterpenes; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neurotoxins; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence; Urodynamics

To compare PGP9.5 and transient receptor potential vanilloid receptor (TRPV1) suburothelial immunoreactivity between controls and patients with spinal neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, as suburothelial PGP9.5-staining nerve fibres decrease in patients with spinal NDO who respond to intravesical capsaicin, and TRPV1 is present on these suburothelial nerve fibres in normal and overactive human urinary bladder.. Patients with refractory NDO were enrolled in a prospective, randomized, parallel-group, double-blind, placebo-controlled trial using escalating doses of resiniferatoxin to a maximum of 1 micro mol/L. Flexible cystoscopic bladder biopsies obtained at baseline, 4 weeks after each instillation and at the time of maximum clinical response were compared with biopsies taken from control subjects. Frozen sections were incubated with rabbit antibodies to TRPV1 and PGP9.5, and assessed using standard immunohistochemical methods. PGP9.5 nerve density was analysed using a nerve-counting graticule by an observer unaware of sample origin. Another two independent observers unaware of each other's results used a random grading scale to evaluate TRPV1 nerve fibre density and intensity. The immunohistochemistry results were compared with histology findings (haematoxylin-eosin), and the Mann-Whitney test used to assess any differences (P < 0.05 significant) and the Pearson test for correlation.. There were eight controls and 20 patients with spinal NDO, 14 (five clinical responders and nine not) who received the maximum dose of resiniferatoxin. There were more PGP9.5 and TRPV1 nerve fibres in patients with NDO than in controls (P = 0.007 and 0.002, respectively). Immunoreactivity before resiniferatoxin was similar in both groups for both PGP9.5 and TRPV1. In responders there were fewer PGP9.5 and TRPV1-positive fibres after treatment (P = 0.008 for each) but no change in those not responding. Changes after treatment for TRPV1 correlated well with those for PGP9.5 (r = 0.88, P < 0.001).. The decrease of PGP9.5 and TRPV1 immunoreactive nerve fibres in responders to resiniferatoxin (to levels in control tissues) suggests that the increased numbers of nerve fibres in patients with NDO are mainly of sensory origin and express TRPV1. As baseline nerve fibre values were similar in responders and nonresponders, an additional factor may account for the difference in treatment outcome.

Topics: Administration, Intravesical; Biomarkers; Biopsy; Diterpenes; Double-Blind Method; Humans; Immunohistochemistry; Ion Channels; Middle Aged; Neurotoxins; Prospective Studies; Receptors, Drug; TRPV Cation Channels; Ubiquitin Thiolesterase; Urinary Bladder; Urinary Bladder, Neurogenic; Urinary Incontinence

Current pharmacologic treatment of detrusor overactivity relies on anticholinergic drugs. However, they often have untolerable side effects so that they are administered in doses insufficient to restore urinary continence. Recently, intravesical instillations and injections into the detrusor muscle of new pharmacological agents have been developed. The present study report our own experience in the treatment of detrusor overactivity with intravesical administrations of vanilloid agents and with botulinum-A toxin injections into the detrusor muscle in a group of spinal cord injured patients. In particular, we compared the clinical and urodynamic effects of the 2 drugs in an attempt to find a new and valid therapeutic option in those cases unresponsive to conventional treatment.. Seventy-five patients with spinal cord injury and refractory detrusor overactivity were included in the study: 35 patients received repeated intravesical instillations of resiniferatoxin (RTX) dissolved in normal saline; 40 patients received repeated injections of 300 units botulinum A-toxin diluted in 30 ml normal saline. Clinical assessment and urodynamics were performed at baseline and 6, 12 and 24 months after treatment.. With both treatments there was a significant reduction in mean catheterization and episodes of incontinence and a significant increase in mean first involuntary detrusor contraction and in mean maximum bladder capacity at 6, 12 and 24 months after therapy. We did not detect any local side effects with either treatment. Botulinum-A toxin significantly reduced also the maximum pressure of uninhibited detrusor contractions more than RTX at all follow-up time points.. In patients with spinal cord injury and refractory detrusor overactivity intravesical RTX and botulinum-A toxin injections into the detrusor muscle provided beneficial clinical and urodynamic results with reduction of detrusor overactivity and restoration of urinary continence in most patients. Botulinum-A toxin injection provided better clinical and urodynamic benefits than intravesical RTX.

Topics: Administration, Intravesical; Botulinum Toxins, Type A; Diterpenes; Female; Humans; Male; Muscle, Smooth; Neuromuscular Agents; Neurotoxins; Urinary Bladder, Neurogenic

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.. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Botulinum Toxins, Type A; Diterpenes; Female; Humans; Injections, Intralesional; Male; Middle Aged; Neuromuscular Agents; Neurotoxins; Prospective Studies; Urinary Bladder, Neurogenic; Urodynamics

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).. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Aged; Diterpenes; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Hypertonia; Nerve Fibers, Unmyelinated; Nervous System Diseases; Neurotoxins; Pain Measurement; Risk Factors; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder; Urinary Bladder, Neurogenic; Urodynamics

Topics: Botulinum Toxins, Type A; Capsaicin; Diterpenes; Humans; Urinary Bladder, Neurogenic; Urinary Bladder, Overactive

To understand the effect of resiniferatoxin on neurogenic bladder by intravesical filling.. Twenty-four male spinal cord injury patients with an obviously low cystometric capacity, 2 incomplete cervical cord injury, 5 complete thoracic cord injury, 4 incomplete thoracic cord injury, 5 incomplete lumbar cord injury and 8 complete lumbar cord injury were examined. The age range was 24 - 58 years old and the course of disease 1 - 6 years. There were 0.0063 mg/4 ml RTX in each bottle, it was dissolved in 50 ml physiologic saline and was infused into bladder slowly, kept 30 min, then was discharged by intermittent catheterization (IC). During the process, the patients were requested to fill a micturition chart and conduct urodynamic examination before and after the infusion. We regulated that it was utility when the amount of increased maximal cystometric capacity (MCC) exceeded or was 100 ml, otherwise it was invalid.. The urodynamic examination before intravesical filling and 1 week after intravesical filling showed that the average MCC were (210 ± 23) ml and (360 ± 30) ml respectively, the average bladder compliance were (17 ± 3) ml/cm H2O and (24 ± 5) ml/cm H2O, there were statistic difference between them (both P < 0.01). The overall effective rate was 62.5%. It lasted 1 - 4 months.. Resiniferatoxin is effective to increase the cystometric capacity and booster the bladder compliance.

Topics: Adult; Compliance; Diterpenes; Humans; Male; Middle Aged; Treatment Outcome; Urinary Bladder; Urinary Bladder, Neurogenic; Urodynamics

Recently, a temporal "coherent" fractal structure and synchronization of rhythms were proposed as two essential indicators for efficient voiding during micturition in female rats. The former was correlated with the intensity and the latter the frequency of physiological signals embedded in random noise. Studies using both indices confirmed that synergic co-activations of bladder and external urethral sphincter (EUS) of female rats were present during the voiding of urine. Therefore, it would be interesting to investigate if these two criteria could be used in the performance evaluation of pharmacological effects on spinal cord-injured rats during micturition. In this paper, the primary goals were to (1) examine if the involved muscles in the lower urinary tract would be under similar synergic co-activations during the administration of capsaicin (CAP) and resiniferatoxin (RTX), and (2) characterize quantitatively the differences of their nervous responses simultaneously. A total of 62 micturition experiments were performed on sixteen spinal cord-injured adult female Sprague-Dawley rats, and then the electromyograms of EUS and cystometrograms of bladder were analyzed. Results based on the aforementioned criteria indicated that the synergy of bladder and EUS during micturition by using RTX was better than that of the CAP. Furthermore, the residue urine volumes for rats under the former treatment were smaller than those of the rats under the latter treatment. Consequently, we concluded that the administration of RTX was more effective than CAP in facilitating voiding in the spinal cord-injured rats.

Topics: Animals; Capsaicin; Disease Models, Animal; Diterpenes; Electromyography; Female; Models, Biological; Rats; Rats, Sprague-Dawley; Sensory System Agents; Spinal Cord Injuries; Urethra; Urinary Bladder; Urinary Bladder, Neurogenic; Urination

Resiniferatoxin (RTX), a vanilloid compound and agonist of the transient receptor potential channel 1 (TRPV1), is known for its beneficial effects on neurogenic detrusor overactivity. The mainstream rationale for its use is the desensitization of TRPV1 on sensory bladder afferents. However, recent findings showed that TRPV1 is present in other cell types in the bladder. To eliminate the effects of RTX on spinal and central neural circuits, we investigated autonomous contractility in normal and neurogenic rat bladders after treatment with RTX.. Female Wistar rats were made paraplegic at vertebral level T8-T9. Animals were intravesically pre-treated with vehicle (ethanol 5%) or RTX (100 nM) and sacrificed after 72 hr. Each bladder was excised and placed in a heated organ bath, where intravesical pressures were measured. Effects on contractile parameters of intravesical volume load, the non-selective muscarinic receptor agonist carbachol (CA) and electrical stimulation (ES) of nerves were studied in both groups.. In RTX-treated normal bladders we found shorter contractions with higher amplitude than in control bladders (P < 0.05). In RTX-treated neurogenic bladders the amplitude and duration of autonomous contractions were increased compared with controls (P < 0.05). Furthermore RTX induced an increased response to CA and to ES (P < 0.05).. RTX significantly affected the properties of autonomous bladder contractile activity. This provides evidence for local effects of RTX on bladder contractile activity, which are not mediated by afferent neural pathways and which may contribute to the beneficial effects on detrusor overactivity. TRPV1 and TRPV1(+) cells seem to play an important role in (autonomous) bladder contractility.

Topics: Animals; Carbachol; Cholinergic Agonists; Diterpenes; Electric Stimulation; Female; Muscle Contraction; Neurotoxins; Rats; Rats, Wistar; TRPV Cation Channels; Urinary Bladder; Urinary Bladder, Neurogenic; Urodynamics

Prospective urodynamic investigation before and after intravesical resiniferatoxin instillation treatment.. 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.. Spinal Cord Injury Unit, Yonsei Rehabilitation Hospital, Seoul, Korea.. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Diterpenes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Retrospective Studies; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urodynamics

To study TRPV1 immunoreactivity in the urothelium of patients with neurogenic detrusor overactivity (NDO) before and after treatment with resiniferatoxin (RTX) and controls. Functional capsaicin TRPV1 receptors have been demonstrated in urothelial cells of rodent urinary bladder, and TRPV1-knockout mice exhibit diminished nitric oxide and stretch-evoked adenosine triphosphate release from urothelial cells. In patients with NDO, TRPV1 suburothelial nerve density is increased, which is reversed by successful treatment with intravesical RTX. However, the role of urothelial TRPV1 in human bladder disorders is unknown.. Flexible cystoscopic bladder biopsies were obtained from 14 patients with NDO before and after treatment with RTX and from 8 control patients. Using a specific antibody for immunostaining, TRPV1 immunoreactivity in the urothelium was quantified by image analysis.. TRPV1 immunoreactivity was observed in basal and apical urothelial cells. Basal cell layer TRPV1 immunoreactivity was significantly increased in NDO compared with control bladders (P = 0.003). In 5 patients who responded clinically to RTX, basal cell layer and total urothelial TRPV1 immunoreactivity decreased significantly after treatment (P = 0.032 and P = 0.016, respectively). The decreases in the basal cell layer TRPV1 immunoreactivity after RTX were comparable to the decreases in suburothelial TRPV1 nerve fibers in the biopsies previously studied from the same patients.. Increased urothelial TRPV1 in patients with NDO may play a role in the pathophysiology, in concert with increased TRPV1 nerve fibers. Although it is not known whether similar pathogenic mechanisms are involved in the increase of urothelial and neuronal TRPV1, both may be targeted by successful RTX therapy.

Topics: Administration, Intravesical; Adult; Biopsy; Cell Polarity; Cystoscopy; Diterpenes; Female; Humans; Image Processing, Computer-Assisted; Immunoenzyme Techniques; Ion Channels; Male; Middle Aged; Nerve Fibers; Single-Blind Method; TRPV Cation Channels; Urinary Bladder; Urinary Bladder, Neurogenic; Urothelium

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.. 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.. 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.. Multiple intravesical instillations of 10 nmol/L resiniferatoxin are effective in treating patients with DO refractory to anticholinergics.

Topics: Administration, Intravesical; Cholinergic Antagonists; Diterpenes; Drug Resistance; Feasibility Studies; Humans; Treatment Outcome; Urinary Bladder Neck Obstruction; Urinary Bladder, Neurogenic; Urinary Incontinence

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.. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Aged; Capsaicin; Diterpenes; Female; Humans; Male; Middle Aged; Neurotoxins; Retrospective Studies; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence

The ATP-gated purinergic receptor P2X3 is expressed by small diameter sensory neurons and has been identified in normal and neurogenic human bladder suburothelial fibres. Animal models have shown that ATP is released by the urothelium during bladder distension, suggesting a mechanosensory role for P2X3 receptors in normal bladder function. Successful treatment of spinal neurogenic detrusor overactivity (NDO) with intravesical resiniferatoxin (RTX), which partly acts on suburothelial C fibres, provides evidence for the emergence of a C fibre-mediated spinal reflex. The aim of this study was to investigate the possible role of P2X3-positive innervation in this pathological voiding reflex by comparing suburothelial P2X3 immunoreactivity of controls and in patients with NDO before and after intravesical RTX.. Bladder biopsies were obtained from 8 controls and 20 patients with refractory NDO enrolled in a trial of intravesical RTX. P2X3 nerve fibre density and intensity were studied in the specimens by immunohistochemistry.. P2X3-IR nerve fibres were significantly increased in patients with NDO compared to controls (p=0.014). Thirteen patients had pre- and post-RTX biopsies available for immunohistochemistry; 5 of them responded clinically and 8 were non-responders. In the 5 patients who responded to RTX, there was a significant decrease in P2X3-positive fibres (p=0.032), whereas in non-responders, P2X3-IR nerve fibre density did not change significantly.. In patients with NDO, the numbers of P2X3-IR nerve fibres were increased in the suburothelium. There was a significant decrease in P2X3 immunoreactivity in responders to RTX, indicating a potential pathophysiological role for the P2X3 expressing fibres.

Topics: Diterpenes; Humans; Immunohistochemistry; Middle Aged; Muscle, Smooth; Neurotoxins; Receptors, Purinergic P2; Receptors, Purinergic P2X3; Urinary Bladder, Neurogenic

Topics: Adult; Anesthesia, Epidural; Anesthetics, Local; Diterpenes; Humans; Lidocaine; Male; Reflex, Abnormal; Urinary Bladder, Neurogenic

Topics: Administration, Intravesical; Animals; Capsaicin; Diterpenes; Ethanol; Muscle Hypertonia; Sodium Chloride; Solvents; Urinary Bladder, Neurogenic

To investigate the therapeutic effect of resiniferatoxin in patients with chronic spinal cord lesions, as detrusor hyper-reflexia and external sphincter dyssynergia (DESD) are common phenomenon in such patients.. Twenty patients with chronic spinal cord lesions and DESD refractory to anticholinergic treatment were enrolled in a prospective study. They were treated with 30 mL of 10 micro mol/L resiniferatoxin for 30 min. Four types of response were recorded during instillation: type 1, a sustained high-pressure detrusor contraction followed by complete acontractility; type 2, a high-pressure contraction followed by progressively lower contractions; type 3, intermittent high-pressure detrusor contractions throughout the instillation; type 4, intermittent low-pressure detrusor contractions. The changes in clinical symptoms and urodynamics at baseline, during resiniferatoxin instillation and 1 month after treatment were compared.. All patients had DESD and 10 had autonomic dysreflexia; 18 had urinary incontinence and 13 had difficult urination. Continence and/or difficult urination improved in 12 patients, including all five with type 1, four with type 2, two with type 3 and only one with a type 4 response. Four patients became dry during the day and eight had less urgency and fewer incontinence episodes, and a significantly increased voided volume. Of the 13 patients who complained of difficult urination, eight had an improvement either by spontaneous voiding (five) or the Crede manoeuvre to voiding (three). The mean (sd) maximum cystometric capacity increased significantly after treatment, from 102.1 (31.5) to 236.6 (88.6) mL (P < 0.001), but the detrusor pressure showed no significant change, at 55.9 (23.2) to 47.5 (28.1) cmH2O. The external urethral sphincter showed intermittent activity during reflexic detrusor contractions at baseline.. Resiniferatoxin at 10 micro mol/L has a clinical effect on two-thirds of patients with a spinal cord lesion and detrusor hyper-reflexia, but not on the DESD. The initial response to resiniferatoxin instillation might predict a favourable therapeutic outcome.

Topics: Administration, Intravesical; Adult; Aged; Ataxia; Cholinergic Antagonists; Chronic Disease; Diterpenes; Drug Resistance; Female; Humans; Male; Middle Aged; Prospective Studies; Reflex, Abnormal; Spinal Cord Diseases; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence; Urination; Urodynamics

Topics: Administration, Intravesical; Child; Diterpenes; Humans; Male; Neural Tube Defects; Neurotoxins; Urinary Bladder, Neurogenic

Resiniferatoxin (RTX), a substance isolated from some species of Euphorbia, a cactus-like plant, shows pharmacological effects similar to those of capsaicin. We have studied the possibility of treating detrusor hyperreflexia refractory to intravesical capsaicin in patients with chronic spinal cord injuries, thereby providing insight into the mechanism of action of RTX on sensory neurons and its possible future pharmacological and clinical use.. RTX saline solution (30 ml at a concentration of 10(-5) M) was instilled into the bladder of 7 patients with detrusor hyperreflexia, refractory to intravesical capsaicin therapy, and left in place for 30 min. Effects on bladder function were monitored during the treatment and at follow-up (15 days and 4 weeks later).. Fifteen days after RTX, the mean cystomanometric capacity increased significantly from 190 ml +/- 20 ml to 407.14 ml +/- 121.06 (p < 0.01), and it remained high four weeks later (421.66 +/- 74.40 p < 0.01). After 15 days, four patients had a pharmacologically induced detrusor areflexia. They emptied their bladders by clean intermittent catheterization. After four weeks, only two patients still had a pharmacologically induced detrusor areflexia. Clinically, three patients remained dry, and the other three reported a significant improvement in their incontinence and symptoms (frequency, urgency and nocturia).. By interfering with sensory unmyelinated fibers, intravesical RTX seems to be a promising treatment option for selected cases of detrusor hyperreflexia. The ideal dosage and treatment interval have not yet been established, and further studies are necessary to confirm our preliminary results.

Topics: Administration, Intravesical; Adult; Capsaicin; Diterpenes; Female; Humans; Male; Neurotoxins; Reflex, Abnormal; Spinal Cord Diseases; Time Factors; Urinary Bladder; Urinary Bladder, Neurogenic; Urodynamics