resiniferatoxin and Multiple-Sclerosis

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

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

To determine the morphology of bladder mucosa and the integrity of its mucin coat in patients with detrusor hyper-reflexia treated with intravesical resiniferatoxin.. Seven patients with detrusor hyper-reflexia were treated intravesically with resiniferatoxin dissolved in 10% ethanol in saline (50 nmol/L solution in two and 100 nmol/L in five). Patients were clinically evaluated by a voiding chart and filling cystometry before and 3 months after each resiniferatoxin application. In addition, they underwent cystoscopy and bladder biopsies at 22-33 months after the first instillation and at 7-23 months after the last one. Tissue samples for light microscopy were fixed in 4% paraformaldehyde, embedded in paraffin and stained with haematoxylin-eosin or periodic acid-Schiff reagent (PAS). Those for electron microscopy were fixed in 5% glutaraldehyde and embedded in resin.. The resiniferatoxin instillation was not painful. Three months after treatment the mean voiding frequency decreased and five incontinent patients became continent. The maximum cystometric capacity increased in all patients; at cystoscopy the bladders appeared normal. On light microscopy the urothelium was of normal morphology and stained with PAS in the luminal cells and in the basement membrane. Mononuclear inflammatory cells were occasionally apparent in the lamina propria. On electron microscopy epithelial cells were visible in a thick basal lamina. Superficial cells had the usual irregular contour and contained numerous membrane-coated vesicles. In the lamina propria, unmyelinated axonal profiles with occasional varicosities could be identified.. Intravesical resiniferatoxin improved urinary frequency, incontinence and bladder capacity in patients with detrusor hyper-reflexia, causing no morphological change in the bladder mucosa. The PAS reactivity of the carbohydrate moieties present in the mucin coat and the basement membrane was unchanged by resiniferatoxin.

Topics: Administration, Intravesical; Adult; Biopsy; Diterpenes; Female; Humans; Male; Microscopy; Microscopy, Electron; Middle Aged; Mucous Membrane; Multiple Sclerosis; Neurotoxins; Reflex, Abnormal; Urinary Bladder; Urinary Bladder Diseases