Combination of a Rapidly Penetrating Agonist and a Slowly Penetrating Antagonist Affords Agonist Action of Limited Duration at the Cellular Level

The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis

The immune response against Trichinella spiralis at the intestinal level depends on the CD4⁺ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE₂, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response.

The effects of intra-articular resiniferatoxin on monosodium iodoacetate-induced osteoarthritic pain in rats

This study was performed to investigate whether an intra-articular injection of transient receptor potential vanilloid 1 (TRPV1) receptor agonist, resiniferatoxin (RTX) would alleviate behavioral signs of arthritic pain in a rat model of osteoarthritis (OA). We also sought to determine the effect of RTX treatment on calcitonin gene-related peptide (CGRP) expression in the spinal cord. Knee joint inflammation was induced by intra-articular injection of monosodium iodoacetate (MIA, 8 mg/50 microl) and weight bearing percentage on right and left hindpaws during walking, paw withdrawal threshold to mechanical stimulation, and paw withdrawal latency to heat were measured to evaluate pain behavior. Intra-articular administration of RTX (0.03, 0.003 and 0.0003%) at 2 weeks after the induction of knee joint inflammation significantly improved reduction of weight bearing on the ipsilateral hindlimb and increased paw withdrawal sensitivity to mechanical and heat stimuli. The reduction of pain behavior persisted for 3~10 days according to each behavioral test. The MIA-induced increase in CGRP immunoreactivity in the spinal cord was decreased by RTX treatment in a dose-dependent manner. The present study demonstrated that a single intra-articular administration of RTX reduced pain behaviors for a relatively long time in an experimental model of OA and could normalize OA-associated changes in peptide expression in the spinal cord.

Effects of Combination Treatment of Intravesical Resiniferatoxin Instillation and Hydrodistention in Patients with Refractory Painful Bladder Syndrome/Interstitial Cystitis: A Pilot Study / 대한배뇨장애요실금학회지

PURPOSE: Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disabling disease of the urinary bladder, and its etiology and treatment are not yet established. Current medications used in the treatment of PBS/IC have shown limited efficacy. This prospective study investigated the efficacy of intravesical resiniferatoxin (RTX) in PBS/IC refractory to medical treatment. METHODS: Patients with proven PBS/IC refractory to traditional medical treatment were enrolled. By randomized trial, a total of 18 consecutive patients were divided into two groups: treatment with hydrodistention and intravesical RTX (group 1) or treatment with hydrodistension only (group 2). We assessed bladder pain by use of a visual analogue pain scale, the maximal urine flow rate, post-void residual urine volume, and a voiding diary before and 3 months after treatment. RESULTS: The median age of the 18 patients was 55.8+/-6.9 years, and the median duration of symptoms before diagnosis was 3.6+/-1.6 years. Frequency, functional bladder capacity, and score on a 5-point pain scale were significantly improved at 3-month after treatment in both groups. Intravesical RTX instillation plus hydrodistention, compared with hydrodistention only, did not have a significant effect on the voiding symptoms or uroflowmetry of the patients but significantly improved scores on the pain scale. CONCLUSIONS: Intravesical RTX instillation plus hydrodistention was effective in relieving pain but was not effective in improving lower urinary tract symptoms. Further larger studies are needed to clarify the efficacy of combination treatment of intravesical RTX instillation and hydrodistention.

Intravesical instillation resiniferatoxin and hydrodistention for the treatment of interstitial cystitis / 国际外科学杂志

Objective To evaluate the efficacy of bladder hydredistention and resiniferatoxin(RTX)on treating female interstitial cystitis(IC).Methods A total of 16 patients with IC were included.All patients received cystoscopie hydrodistention and RTX under anesthesia.The O'Leary-Sant Interstitial Cystitis Symptom Index(ICSI),Problem Index(ICPI),voiding frequency and the maximum bladder capacity were recorded before and after the therapy.Results All patients were followed up for 1 or 6 months.Fourteen of 16patients'symptoms were relieved,2 patients symptoms disappeared or significantly relieved.Conclusion Bladder hydrodistention and RTX effectively relieve symptoms and improve quality of life in patients with IC in the short term.

Observation and nursing for prevention of cystospasm in patients after prostatic surgery with irrigation of resinieratoxin into urinary bladder / 中国实用护理杂志

Objective To discuss the treatment and nursing effect for prevention of cystospasm in patients after prostatic surgery with irrigation of resinieratoxin (RTX) into urinary bladder. Methods Twenty patients were divided into the control group and observation group with 10 cases in each group according to the date of hospitalization.Four milliliters of RTX and 100 ml of normal saline were irrigated into the bladder 3 days before operation in the observation group.Only 104 ml normal saline was irrigated into the bladder in the control group.The frequency,intension and duration of cystospasm and clearing time of bladder flushing fluid were observed.The international prostatic symptom score (IPSS) and score of life quality were evaluated at the first,second and 4th week after removing of urinary catheter and bladder stoma. Results The outcome in the observation group and the control group were as followed: the incidence rate of cystospasm was 20% and 80%,the clearing time of bladder flushing fluid was (2.8±1.7)d and (5.2±1.0)d,the indwelling time of bladder stoma was (4.0±1.6)d and (5.8±1.1)d,the indwelling time of urinary catheter was (9.3±1.3)d and (11.8±1.1)d,the VAS score was (2.3±1.3)d and (4.6±1.1)d, the IPSS score at the first,second and 4th week were (11.1±3.3)and (16.0±3.0), (9.5±1.4) and (12.7±13.2), (8.4±1.6) and (11.3±2.7),the score of life quality at the 4th week was (1.6±0.5) and (2.8±0.9), respectively. All the above results had statistical difference between the observation group and the control group (P<0.05). Conclusion Standard bladder irrigation,rigorous monitoring of patients condition and maintenance of smooth flush of bladder were the important nursing basis to ensure the exertion of best effect of RTX irrigation.

The Effect of Botulinum Toxin and Resiniferatoxin on the Detrusor Overactivity Induced by Cyclophosphamide in Rat Bladder / 대한비뇨기과학회지

PURPOSE: The purpose of this study was to compare the effects of resiniferatoxin (RTX) and botulinum toxin (BTX) on the bladder detrusor function in a cyclophosphamide (CYP)-induced cystitis rat model. MATERIALS AND METHODS: Sprague-Dawley rats were divided into 5 groups (1: saline treated, 2: CYP and BTX treated, 3: CYP and RTX treated, 4 and 5: CYP treated and sham operated as the counterpart of groups 2 and 3, respectively, with normal saline). 100mg/kg CYP was injected every third day for five weeks. Cystometrograms were performed after the BTX and RTX treatments. RESULTS: 1. The normal control group and the CYP-treated only group. In the CYP-treated group, the time of micturition frequency, the maximal detrusor pressure on the cystometergram (Pvesmax at CMG), the maximal detrusor pressure on the pressure-flow study (Pvesmax at pr/flow) and the episodes of irregular contractions were increased. 2. The CYP-only group and the CYP/BTX or CYP/RTXtreated groups. In the CYP/BTX or CYP/RTX treated groups, the time of micturition frequency, the Pvesmax at CMG, the Pvesmax at pr/flow and the episode of irregular contractions were decreased. 3. The CYP/BTXtreated group and the CYP/ RTXtreated group. There was no statistically significant difference between the two groups regarding micturition frequency, the PvesMax at CMG and the PvesMax at pr/flow, the Dhfo and the episodes of involuntary contractions (p>0.05). CONCLUSIONS: Intravesical administration of BTX or RTX blocked the CYP-induced detrusor overactivity as was shown by the restoration of the micturition frequency, the intravesical pressure and the involuntary contraction episodes to a control level. There was no statistically significant difference between the two groups regarding the urodynamic parameters.

Intravesical instillation resiniferatoxin for the treatment of patients with idiopathic overactive bladder:a randomized,placebo controlled clinical trial / 中国基层医药

Objective To evaluated the clinical outcomes of intravesical instillation resiniferatoxin(RTX) for the treatment of patients with idiopathic overactive bladder(IOAB).Methods 26 cases with IOAB were randomly divided into test(A,14 cases) and control(B,12 cases) groups.The patients in group A were treated by intravesical instillation with 40ml of 0.5% idocain retained within the bladder for 3 minutes at first and with 100ml of 100nmol/L RTX retained within the bladder for 30 minutes late.The patients in group B were treated by the same method,however,the furacilin solution(placebo) at a dilution 1∶5000 was used instead of 100nmol/L RTX.The efficacy(daily voiding frequency,urgent uresis,FDV,MCBC,Qmax) of the 2 groups were evaluated before,1 month and 3 months after treatment.Results The pre-treatment comparion with prost-treatmen at 1 month and 3 months of A group was significant(P0.05).14 patients(54%) had slightly stimulating symptom in the urethra or bladder,and were otherwise generally well tolerated.Conclusion Single administration of RTX is safe and effective in patients with IOAB.

Resiniferatoxin inhibits neuropeptide expression in rat with prostatitis / 第三军医大学学报

Objective To study the therapeutic effect of resiniferatoxin(RTX)on prostatic pain from chronic prostatitis.Methods Complete Freund's adjuvant(CFA)was injected into rat bilateral ventral prostate to form chronic prostatic inflammation in 15 male SD rats.Two weeks later,RTX was injected into lumbosacral vertebral canal(n=5)or bilateral ventral prostate(n=5).Another 5 SD rats served as normal control.Neuropeptide level and the mRNA expression of substance P(SP)and calcitonin gene-related peptide(CGRP)in lumbosacral spinal cord and dorsal root ganglia(DRG)were measured by immunohistochemistry,radioimmunoassay,and RT-PCR.Results SP and CGRP level and their mRNA expression increased significantly in rat with prostatitis.Neuropeptide level and their mRNA expression were decreased after RTX was injected into vertebral canal and prostate.Conclusion Local injection of RTX can effectively inhibit synthesis and release of SP and CGRP,suggesting that RTX may be helpful to the analgesic therapy of chronic prostatitis.

The Resininferatoxin Therapy for the Hyperreflexive Neurogenic Bladder: Report of two cases of spinal cord injured patients

Resiniferatoxin, a substance isolated from some species of Euphorbia, a cactus-like plant, shows pharmacological effects similar to those of capsaicin. We administered resiniferatoxin for treating detrusor hyperreflexia to patient with chronic spinal cord injury. Resiniferatoxin solution (100 ml at a concentration of 10-7, 10-6 M) was instilled twice into the bladder of patient with detrusor hyperreflexia and left in place for 30 minutes. Effects on bladder function were monitored at 1 month later follow-up. One month after the last resiniferatoxin instillation, patients reported a significant symptomatic improvement of their incontinence and increased mean bladder capacity.

Intravesical instillation of resiniferatoxin for the treatment of overactive bladder / 中华泌尿外科杂志

Objective To evaluate the clinical outcomes of intravesical instillation of resiniferatoxin (RTX) for the treatment of overactive bladder(OAB). Methods 30 patients (28 females and 2 males) included in the study.The mean age was 39 years (range,21 to 60 years).The mean course of the illness was 6.9 years (range,2 to 30 years).The voiding diaries of pretreatment showed that frequency at day time varied from 9 to 26 times with a mean of 15.0 times;frequency at night ranged from 3 to 13 times with a mean of 6.4 times.Of the 12 patients undergoing cystoscopy 10 had chronic inflammation in both mucous and submucous.Based on biopsy 1 case was pathologically diagnosed as glandulous cystitis,2 as interstitial cystitis,and others as chronic inflammation.100 ml of RTX at a concentration of 100 nmol/L was intravesically instillated in all the patients and was retained within the bladder for 30 minutes. Results RTX instillation had no vesical irritation and other adverse effects,and no local anesthesia was required.The symptoms were improved immediately in all the patients after 1 day of RTX intervention.The decreases in both diurnal (5 to 15 times,mean 8.9 times) and nocturnal (0 to 5 times,mean 3.0 times) frequencies were significant(P