resiniferatoxin and Urination-Disorders

Myogenic activity, distention of the detrusor, and signals from the urothelium may initiate voiding. In the bladder, afferent nerves have been identified not only in the detrusor, but also suburothelially, where they form a plexus that lies immediately beneath the epithelial lining. Extracellular adenosine triphosphate (ATP) has been found to mediate excitation of small-diameter sensory neurons via P2X3 receptors, and it has been shown that bladder distention causes release of ATP from the urothelium. In turn, ATP can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably, not only ATP but also a cascade of inhibitory and stimulatory transmitters and mediators are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. These mechanisms may be targets for future drugs. The central nervous control of micturition involves many transmitter systems, which may be suitable targets for pharmacologic intervention. gamma-Aminobutyric acid, dopamine, enkephalin, serotonin, and noradrenaline receptors and mechanisms are known to influence micturition, and potentially, drugs that affect these systems could be developed for clinical use. However, a selective action on the lower urinary tract may be difficult to obtain. Most drugs currently used for treatment of detrusor overactivity have a peripheral site of action, mainly the efferent (cholinergic) neurotransmission and/or the detrusor muscle itself. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis, as well as in the aging bladder, a noncholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions.

Topics: Animals; Capsaicin; Cats; Diterpenes; Humans; Muscle Contraction; Muscle, Smooth; Neurons, Afferent; Rats; Receptors, Purinergic; Tachykinins; Urinary Bladder; Urinary Bladder Diseases; Urinary Tract; Urinary Tract Physiological Phenomena; Urination; Urination Disorders; Urothelium

Topics: Administration, Intravesical; Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Botulinum Toxins; Capsaicin; Cholinergic Antagonists; Cresols; Cystitis, Interstitial; Diterpenes; Humans; Mandelic Acids; Neurotoxins; Phenylpropanolamine; Tolterodine Tartrate; Urinary Bladder; Urinary Bladder Diseases; Urination Disorders

Topics: Animals; Capsaicin; Cats; Diterpenes; Humans; Rats; Reflex, Abnormal; Urinary Bladder Diseases; Urination Disorders

Present therapeutic approaches to control hypersensitive disorder of the lower urinary tract and bladder pain are clinically and scientifically unsatisfactory. We performed a randomized placebo controlled study with followup after 1 and 3 months using intravesical resiniferatoxin to treat hypersensitive disorder and bladder pain.. We prospectively randomized 18 patients into 2 groups to receive a single dose of 10 nM. resiniferatoxin intravesically (group 1) or a placebo saline solution only (group 2). All patients had at least a 6-month history of frequency, nocturia, urgency and symptoms of pelvic pain as well as no urinary tract infection within the last 3 months, functional disorders of the lower urinary tract, or other vesical or urethral pathology. Pretreatment voiding pattern and pain score were recorded. Patients were evaluated after 30 days (primary end point) and 3 months (secondary end point).. The 2 groups were adequately homogeneous in regard to patient age, sex ratio, disease duration, voiding pattern and pain score. At the primary end point mean frequency plus or minus standard error of mean was decreased from 12. 444 +/- 0.70 voids to 7.111 +/- 0.67 and nocturia from 3.777 +/- 0. 27 to 1.666 +/- 0.16 (p <0.01). We observed a lesser significant improvement in mean frequency in group 1 at the secondary end point to 10.444 +/- 0.94 voids (p <0.05). No significant modification was noted in patients assigned to placebo. Mean pain score significantly decreased in group 1 at the primary end point from 5.555 +/- 0.29 to 2.666 +/- 0.23 (p <0.01) but not at the secondary end point (4.777 +/- 0.66, p >0.05). No statistically significant improvement in mean pain score was observed in placebo group 2. During resiniferatoxin infusion 4 group 1 patients noticed a light warm or burning sensation at the suprapubic and/or urethral level.. Intravesical resiniferatoxin may significantly improve the voiding pattern and pain score in patients with hypersensitive disorder and bladder pain. Because resiniferatoxin did not cause a significant warm or burning sensation at the suprapubic and/or urethral level, it may be considered a new strategy for treating hypersensitive disorder and bladder pain. However, further studies are necessary to confirm our results and define the resiniferatoxin mechanism of action, dose and necessary treatment schedule.

Topics: Administration, Intravesical; Adult; Analysis of Variance; Diterpenes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neurotoxins; Pain Measurement; Pelvic Pain; Placebos; Prospective Studies; Urinary Bladder Diseases; Urinary Catheterization; Urination; Urination Disorders; Urodynamics

To evaluate the effect of bladder C-fiber desensitization on BPH-associated storage LUTS.. Twelve patients with predominant BPH-associated storage LUTS gave written informed consent to enter the study. IPSS and QoL scores, micturition chart, uroflowmetry, cystometry and post-void residual (PVR) were obtained at baseline and at 1, 3 and 6 months after a single intravesical administration of 50 nM resiniferatoxin (RTX) solution.. Mean IPSS score decreased from 20.1 +/- 6.0 to 10.5 +/- 4.4 at 1 month (p = 0.0001), to 10.3 +/- 4.4 at 3 months (p = 0.00001) and to 9.8 +/- 5.7 at 6 months (p < 0.00001). Mean QoL score decreased from 4.5 +/- 1 to 2.5 +/- 1 at 1 month (p = 0.0001), to 2.3 +/- 1 at 3 months (p = 0.0004) and to 2.6 +/- 1.2 at 6 months (p = 0.0003). Mean urinary frequency decreased from 15.2 +/- 8.5 to 10.8 +/- 7.3 at 1 month (p = 0.0002), to 10.2 +/- 4.9 at 3 months (p = 0.002) and to 11.7 +/- 9.2 at 6 months (p = 0.005). Urge incontinence, which was present in six cases, disappeared in 4 patients and decreased to less than half in the other two. Mean first desire to void and maximal cystometric capacity increased significantly after RTX whereas uroflowmetry and PVR were not altered.. Intravesical desensitization of bladder C fibres with intravesical RTX might be useful in the treatment of patients with predominant BPH associated storage LUTS.

Topics: Aged; Diterpenes; Humans; Male; Middle Aged; Nerve Fibers, Unmyelinated; Neurotoxins; Pilot Projects; Prostatic Hyperplasia; Urinary Bladder; Urination Disorders; Urodynamics

Resiniferatoxin (RTX) is a specific C fiber neurotoxin which produces desensitization. In this study we performed intravesical RTX therapy in patients with idiopathic detrusor overactivity. In addition we measured the current perception threshold of C and A delta fibers before and after treatment to evaluate clinical significance.. The protocol involved an RTX solution (100 ml of 50 nM) instilled in the bladder for 30 minutes. Four men and 6 women 59 to 75 years old were treated. Effects on bladder function were evaluated before and 30 days after treatment by cystometry and Neurometer (Neurotron, Inc., Baltimore, Maryland). Subjective and objective measures included bladder diaries and quality of life before treatment, and 7, 30 and 90 days subsequently.. Of the 10 patients 5 noted improvement and 2 of them became dry. The other 5 patients were considered to have stationary symptoms. Mean maximal cystometric capacity +/- SD increased from 229 +/- 108 ml at baseline to 271 +/- 99.5 ml at 30 days (p = 0.04). The mean number of daily episodes of urinary incontinence decreased from 3.5 +/- 2.2 to 2.0 +/- 1.6 (p = 0.008) at 7 days, to 1.9 +/- 1.6 (p = 0.018) at 30 days and to 2.5 +/- 1.7 (p = 0.018) at 90 days. Mean current perception threshold values of C and A delta fibers did not change significantly, from 46.9 +/- 35.2 to 56.4 +/- 32.1 (p = 0.161) and from 66.9 +/- 31.7 to 66.4 +/- 25.2 (p = 0.952), respectively. However, values of C fibers increased in all patients who showed improvement from 46.2 +/- 33.2 to 64.0 +/- 36.8 (p = 0.043).. Intravesical RTX improved bladder capacity and leak episodes in patients with idiopathic detrusor overactivity. Intravesical RTX is a promising treatment for this condition.

Topics: Administration, Intravesical; Aged; Diterpenes; Female; Humans; Male; Middle Aged; Nerve Fibers, Unmyelinated; Neurotoxins; Urination Disorders; Urodynamics

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.. 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.. 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.. 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.

Topics: Administration, Intravesical; Adult; Aged; Aged, 80 and over; Diterpenes; Female; Humans; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Neurotoxins; Urinary Bladder; Urination Disorders; Urodynamics