Dr. Jay Burstein
Dekalb Clinic
217 Franklin St.
Dekalb, IL 60115
815-758-8672

Dr. Jay D. Burstein is a
Board Certified Urologist
specializing in painful voiding syndromes and incontinence.

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Created: June 29 2000
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You are here: IC Network > Q&A with an MD > AUA 200 Comments

AUA 2000- Interstitial Cystitis Research Update 2000

Dr. Burstein has assembled a list of the abstracts presented at this years American Urological Association, including personal comments on each study. It's not only great to see the new and exciting out there, but to also a physician interpret the meaning of some of the research projects for us. Thank you Dr. Burstein!

  1. Increased Production of Bladder Surface Mucin Due to Bladder Trauma
  2. BCG vs. DMSO Instillation Therapy in IC: A randomised double-blind study
  3. Plasma catecholamine concentrations in cats with IC
  4. Single Dose of Intravesical resinferatoxin for the treatment of IC (capsaicin)
  5. The efficacy of intravesical oxybutynin and pentosanpolysulphate in the treatment of IC: A prospective, double-blind study
  6. Psychological stress, urinary symptoms and HPA Axis activation in IC patients.
  7. NF-lB-Dependent upregulation of neurokinin-a receptors in a mouse model of LPS-induced cystitis.
  8. Urine inducted apoptosis in cultured bladder cells
  9. Do intravesical agents used in IC and overactive bladder alter permeability of normal urothelium?
  10. Are glomerulations typical of IC?
  11. Anti-proliferative factor (APF), heparin binding epidemal growth factor-line growth factor (HB-EGF) and Epidermal Growth Factor (EGF) alterations in IC confirmed
  12. Interstitial cystitis or prostatitis? Pentosan polysulfate therapy for male chronic pelvic pain syndrome
  13. Safety and efficacy of 3 doses of pentosan polysulfate in patients with IC
  14. Vaginal surface electromyography analysis in women with IC and vulvodynia treated with myofascial release
  15. Percutaneous S3 nerve root neurostimulation decreases symptoms and normalizeds urinary HB-EGF and APF activity in IC patients.

INCREASED PRODUCTION OF BLADDER SURFACE MUCIN DUE TO BLADDER TRAUMA.

Omid Rofeim, Dolores Shupp-Byrne, Grant S. Mulholland, Robert M. Moldwin. New Hyde Park, NY; Philadelphia, PA.

INTRODUCTION AND OBJECTIVES: Bladder surface mucin (BSM) is a heterogeneous substance composed of proteoglycans, glycosaminoglycans, and glycoproteins. There is strong evidence that this layer protects the underlying urothelium from bacterial invasion, tumor implantation, and noxious agents in the urine. Alterations of BSM are associated with urothelial permeability changes and enhancement of bacterial adhesion. This protective film is commonly disrupted during endoscopic and open urological procedures. We hypothesize that the production of BSM is enhanced as a consequence of bladder trauma, thus facilitating bladder repair. In this study, we analyze changes in a high molecular weight urinary glycoprotein component of bladder surface mucin, GP51, prior to and after hydrodistention.

METHODS: Catheterized urine specimens were obtained from 20 female interstitial cystitis (IC) patients, mean age 55, meeting NIDDK criteria, prior to and immediately following bladder hydrodistention. Urine GP51 concentration was determined using Mab (IgG)/human in an antigen inhibition enzyme-linked immunoabsorbant assay. Urine GP51 levels (mcg/ml) were indexed to urine creatinine (mcg/ml). Six female control patients, mean age 47, submitted urine without hydrodistention.

RESULTS: Pre and post-distention indices were 0.12 (SD 0.2615) and 2.4 (SD 2.876), respectively (p<0.0001). Control index was 0.31 (SD 0.2217).

CONCLUSIONS: Bladder trauma produced by hydrodistention resulted in an immediate increase (mean 28-fold) in urinary GP 51 in all patients, far exceeding the concentration seen in non-IC individuals (IC patients are known to have low urine GP51 concentrations). These data strongly suggest that bladder trauma stimulates the production of at least one component of bladder surface mucin. These findings also suggest that a favorable clinical response to hydrodistention in some IC patients may occur secondary to this phenomenon.

Dr. Burstein's Comment:  Patients frequently ask why hydrodistension works and I answer by saying that during the process, abnormal surface cells are “torn” which allows healing to occur with normal functioning cells. This may be a grossly simplified answer but it appears, as this study suggests, that “stretching” the bladder releases surface mucins that may restore normal function to the bladder lining.


BCG VS DMSO INSTILLATOIN THERAPY IN INTERSTITIAL CYSTITIS: A PROSPECTIVE RANDOMISED DOUBLE-BLIND STUDY.

Mohammad Haghsheno, Holmang Sten, Peeker Ralph, Fall Magnus. Gothenburg, Sweden.

INTRODUCTION AND OBJECTIVES: We conducted a prospective double-blind study with cross-over design of intravesical BCG versus DMSO in order to determine whether or not patients with classic and nonulcer interstitial cystitis (IC), respectively, might benefit from either regimen.

METHODS: Twenty-one patients with IC (11 classic and 10 nonulcer) randomly underwent treatments with intravesical BCG or DMSO and were, if not improved, treated with the other substance after a wash-out period. All 21 patients were evaluated with symptom questionnaires including visual analogue pain scale (VAS) and micturition diaries.

RESULTS: Irrespective of regimen, there was no improvement as to maximal functional capacity. There was a reduction of urinary frequency following DMSO treatment but only in the classic subtype (p<0.05) whereas no reduction was seen following BCG in either subtype. A substantial pain decrease was noticed in classic (p<0.05) as well as nonulcer IC (p<0.05) following DMSO. Pain decrease was also reported after BCG, although not statistically significant (p=0.06).

CONCLUSIONS: Intravesical BCG has been presented as an encouraging new option for the treatment of IC. The present study fails to demonstrate benefit from intravesical BCG treatment. DMSO had no positive effect on maximal functional capacity but resulted in significant reduction of pain and also reduction of urinary frequency although only for patients with classic IC.

Supported by: The Swedish Medical Research Counsil, 09902 and 02235, The Regional Health Authority of West Sweden, The Swedish Society for Medical Research, Gothenburg Medical Society and The Medical Faculty, University of Gothenburg

Dr. Burstein's Comment:  Apparently DMSO was effective in relieving pain, but most patients received multiple treatments and no placebo group was used. I am not convinced that this study proves BCG has no benefit in treating IC . Unfortunately, there has been a lack of patient interest and a major BCG study has been closed. We will just have to wait to further evaluate the usefulness of BCG.


PLASMA CATECHOLAMINE CONCENTRATIONS IN CATS WITH INTERSTITIAL CYSTITIS.

C. A. Tony Buffington. Columbus, OH.

INTRODUCTION AND OBJECTIVES: Interstitial cystitis (IC) is a chronic urologic syndrome affecting humans and domestic cats. We have found increased immunoreactivity to tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, in the locus coeruleus of cats with IC, and increased in vitro release of norepinephrine (NE) from bladder strips. In humans with IC, increased density of bladder sympathetic fibers, increased spinal sympathetic neuron activity, and increased urine NE excretion all have been reported. Based on these results, we tested the hypothesis that plasma catecholamines and their metabolites would be increased in cats with IC.

METHODS: 4 healthy cats and 4 cats with IC were anesthetized and catheters were placed in the external jugular vein. 6 hours after recovery, samples were obtained for HPLC analysis of plasma levels of NE, epinephrine (E), dopamine (DA), dihydroxyphenylglocol (DHPG), dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylalanine (DOPA).

A significant increase in plasma norepinephrine concentration (mean " s.d.) and a trend toward increased epinephrine were found, whereas no effect on the dopaminergic system (DOPA, DA, DOPAC) was identified.

CONCLUSIONS: These results support and extend previous studies identifying an increase in sympathetic activity in patients with IC.

Supported by: NIDDK-DK47538

Dr. Burstein's Comment:   This study demonstrated an increase in sympathetic (“the fight or flight” adrenalin) nervous system activity. There is speculation that the pain of IC may be a primary nervous system abnormality distinct from a discreet bladder disease.


SINGLE DOSE OF INTRAVESICAL RESINIFERATOXIN FOR THE TREATMENT OF INTERSTITIAL CYSTITIS-PRELIMINARY RESULTS OF A RANDOMISED CONTROLLED STUDY.

Massimo Lazzeri, Patrizia Beneforti, Damiano Turini, Guido Barbagli, Enzo Palminteri. Ferrara; Arezzo, Italy.

INTRODUCTION: Intravesical conservative pharmacotherapy remains one of the mainstays in the treatment of Interstitial Cystitis (IC). Recently some clinical effect has been reported by intravesical capsaicin in patients with frequency and nocturia, but it failed to decrease urgency and pain. Here we reported the preliminary results of a single dose of intravesical Resiniferatoxin (RTX), an ultrapotent capsaicin-analogue, used for the treatment of IC in a randomized placebo controlled study.

METHODS: Twelve female patients (mean age 45.5, range 37 to 60), suffering from IC according the Interstitial Cystitis Data Base Study (ICDBS), were randomized to received 30 cc of a saline solution containing 10-8M RTX or placebo (saline solution). The response to treatment was estimated by voiding pattern and a pain score as previously described after 1 and 3 months.

RESULTS: A significant decrease of main pain score was observed at primary (2.16 " 0.40 p<0.01) but not at secondary (4.83 " 0.75) end-points in patients who receive RTX compared to before of the treatment (5.83 " 1.16) and placebo group (4.16 " 1.16 primary end-point). After one month 5 over 6 patients of RTX group reported a significant decrease of frequency, nocturia and urgency; three patients assigned to placebo reported an improvement of frequency and urgency but not of nocturia and pain. After 3 months only two patients, who receive RTX, were moderately satisfactory of their quality of life. No one reported a warm or burning sensation at the soprapubic/urethral level during the infusion of RTX or other significant side effects.

CONCLUSIONS: RTX seems to decrease significantly pain and improve symptoms in patients with IC when compared with placebo. It would be an interesting alternative in the treatment of interstitial cystitis even if other studies, performed on a larger number of patients, are necessary to confirm our results.

Supported by: None

Dr. Burstein's Comment:  Capsaicin and related compounds are the actual chemicals that make peppers hot. They have been shown previously to be effective in decreasing bladder contractions in various neurogenic conditions. Repeated exposure of capsaicin depletes substance P and limits the ability of the nerves to transmit sensation of pain.


THE EFFICACY OF INTRAVESICAL OXYBUTYNIN AND PENTOSANPOLYSULPHATE IN THE TREATMENT OF INTERSTITIAL CYSTITIS: A PROSPECTIVE, DOUBLE-BLIND TRIAL.

Jurjen J. Bade, Frederiek Hollants, Freddy Gerkens, Mardy Eckhardt, Miel Nanlohy, Ton Boon. Oss, The Netherlands; Utrecht, The Netherlands.

PURPOSE: A previous study demonstrated a 44% intravesical Pentosan-polysulphate (PPS) response compared to a 20% placebo response (Br.J.U. 1997, 79:168-171). The rationale to use intravesical Oxybutynin (OX) is based on its strong local anesthetic and anticholinergic qualities. We report the therapeutic efficacy of intravesical PPS compared to intravesical OX in Interstitial Cystitis (IC) patients.

METHODS: Consecutive IC patients diagnosed in two institutions, according to the NIH criteria, were enrolled. Patients were randomised and prospective, double-blind treated with either intravesical PPS (300mg in 50ml) or OX (10mg in 50ml), 3 times a week, during at least 6 months. Evaluation was done using the IC symptom score, a 48-hr voiding log and urodynamic investigation.

RESULTS: Of 24 (22 female/2 male) eligible patients results were available of 21. Two pts went off-study in the OX group, one in the PPS-group. In the PPS group 4 out of 10 patients (40%) responded (subjective) compared to 6 out of 11 pts (55%) in the OX group. Both instillations were well tolerated.

CONCLUSIONS: In this study intravesical OX was well tolerated and efficious in the treatment of IC and superior to intravesical PPS. This is contrary to the general failure of oral anticholinergics in the treatment of IC.

Dr. Burstein's Comment:  Some subjective improvement in both groups. Bladder instillation can be done at home using self-catheterization techniques, but notice that the results showed mild, not dramatic improvement.


PSYCHOLOGICAL STRESS, URINARY SYMPTOMS AND HPA AXIS ACTIVATION IN INTERSTITIAL CYSTITIS PATIENTS.

Susan K. Lutgendorf, Karl J. Kreder, Timothy L. Ratliff, Nan E. Rothrock, Sophie Ligier, Esther Sternberg. Iowa City, IA; Bethesda, MD.

INTRODUCTION AND OBJECTIVES: Although symptom exacerbation with stress has been reported in interstitial cystitis (IC), this has not been tested empirically. Because abnormal hypothalamic-pituitary-adrenal (HPA) function has been reported in diseases having high co-morbidity with IC, we hypothesized that the HPA axis response to stress might be hypoactive in IC and contribute to IC pathophysiology. We studied whether mental stress evoked IC symptom exacerbation and adequacy of the HPA response.

METHODS: Fourteen women with IC (mean age 48) and 14 age-matched controls participated in a laboratory session including a 60 min. post-IV baseline (BL), 25 minutes of mental stressors including a speech task, mental arithmetic and a computer video challenge, and 75 minutes of recovery. Cortisol and ACTH were measured 3 times pre-stressor, and 8 times post-stressor onset. Acute IC symptoms were assessed at 4 voids: 15 minutes pre-stressor, and 25, 70, and 100 minutes post-stressor onset; chronic symptoms were assessed with the IC Data Base symptom survey.

RESULTS: Patients reported significantly greater pain and urgency at all 4 voids (p<0.005), increased pain and urgency from baseline to post-stressor (p<0.005), and sustained symptom elevations over BL (p<0.03). Controls showed no symptom changes with stress. Patients and controls showed no differences in maximum elicited ACTH or cortisol (p>0.40). Greater cortisol at 10 and 25 minutes was related to less pain on urination during the reactivity (p<0.03). Patients with greater maximum elicited cortisol reported less pain on bladder filling (p=0.05), less maximum pain (p<0.05), and less urgency over the last 4 weeks (p=0.08).

CONCLUSIONS: These findings indicate that an acute stressor can elicit pain and urgency in IC patients. Although hypoactivity of the HPA axis to a stress challenge was not observed, cortisol response to a laboratory stressor appears to be related to acute and chronic symptoms.

Supported by: RR00059, General Clinical Research Centers, NCRR, NIH

Dr. Burstein's Comment:   Cortisol is a naturally secreted anti-inflammatory hormone that seems to be produced in abnormally small amounts when patients were exposed to stress. This shows a physiologic reason for pain : “it’s not in your head.”


NF-kB-DEPENDENT UPREGULATION OF NEUROKININ-1 RECEPTORS IN A MOUSE MODEL OF LPS-INDUCED CYSTITIS.

Xiao-Chun Wang, Ricardo Saban, James H. Kaysen, Marcia R. Saban, Patricia L. Allen, Edmund N. Benes, Timothy G. Hammond. New Orleans, LA; Galveston, TX.

INTRODUCTION AND OBJECTIVES: Several lines of evidence suggest a central role for substance P (SP) and the neurokinin 1 (NK-1) receptor as mediators of bladder inflammation. The proteins which constitute the final common pathway linking receptors on cell surfaces to the inflammatory cascade have recently been identified and cloned. Central to activation of this inflammatory cascade is translocation from cytosol to nucleus of the nuclear transcription factor known as nuclear factor-kappa B (NF-kB). This study provides several lines of evidence that lipopolysaccharide (LPS)-induced inflammation of the mouse urinary bladder is mediated by NF-kB upregulation of NK-1 receptors

RESULTS: LPS instillation into the mouse bladder resulted in time-dependent cleavage of inhibitory subunit (IkB) and translocation of NF-kB from the cytosol to the nucleus. This was associated with increased expression of an NF-kB dependent inflammatory component, the neurokinin-1 receptor. Pretreatment of mouse bladders with the NF-kB inhibitor, lactacystin, prevented bladder inflammation, cleavage of IkB, and the increase in NK-1 receptor. Hence, NF-kB mediates many features of urinary bladder inflammation induced by LPS.

CONCLUSIONS: Experimental cytitis secondary to LPS involves NK-kB-dependent upregulation of substance P receptors. The NF-kB cascade is an important target for anti-inflammatory management of cystitis.

Supported by: Supported by the National Institutes of Health: DK51392 (TH) and DK 55828 (RS)

Dr. Burstein's Comment:   There have been multiple studies regarding the role of substance P stimulation and the pain cascade. This study tries to pinpoint the initiation of the cycle . This would be a logical area to study regarding future drug therapy to block the pain using anti-inflammatory agents.


URINE INDUCED APOPTOSIS IN CULTURED BLADDER CELLS.

Paul C. Stein, Sally Bautista, Susumu Tsujino, Jian Zhang, C. L. Parsons. San Diego, CA.

INTRODUCTION AND OBJECTIVES: An epithelial dysfunction has been recognized in interstitial cystitis (IC ) patients. The cause of this defect is not understood. A urinary role in the pathobiological process has been suspected. However, no definitive cytotoxic factors have been isolated or characterized from patients urines, although an anti-proliferative factor has been recently described. Urine exposure might influence apoptosis in bladder cells. Inappropriate regulation on even a relatively small, but persistent scale would produce significant effects on bladder mass and function. This study was done to determine if urine from IC patients can influence apoptosis in bladder cells.

METHODS: Urines (N=15) were collected from patients who fulfilled the NIDDK criteria for IC. Urines were tested undiluted by incubation with urothelial or smooth muscle target cells (1X104/well) for 2-12 hrs. Apoptosis was evaluated by ELISA (anti-histone-nucleosome capture), in-situ staining for fragmented DNA (TUNEL) and staining with annexin-V. Apoptotic urines were further analyzed by dialysis and heat denaturation studies.

RESULTS: Fifteen IC urines were evaluated. There was no apoptotic effect on the smooth muscle cells, whereas, the urines (6/15) induced significant apoptosis in the human (or rat) urothelial cells. Immunochemical and annexin V staining confirmed the ELISA data. RNA was extracted from target cells sufficient for RT-PCR analysis.

CONCLUSIONS: These findings suggest for the first time that urinary factors effect apoptotic pathway in the bladder mucosa. This would impact significantly on urothelial cell populations in the mucosa and therefore would have significance in regulating urothelial cell turnover in interstitial cystitis where the mucosa is believed to be abnormal. These results are also in concordance with our earlier studies that demonstrated cytotoxic urine factors in IC patients and not in normal control urines.

Supported by: Departmental Funds

Dr. Burstein's Comment:   Apoptsis means programmed cell death. Cytotoxic means cell killing. This study suggests that there is something in the urine of IC patients that damages or kills the lining cells of the bladder.


DO INTRAVESICAL AGENTS USED IN INTERSTITIAL CYSTITIS AND AN OVERACTIVE BLADDER ALTER PERMEABILITY OF NORMAL UROTHELIUM?

John G. Calleary, John P. Lavelle, Richard Ramage, Susan A. Meyers, Mark L. Zeidel. Pittsburgh, PA.

INTRODUCTION AND OBJECTIVES: Intravesical agents have been advocated for interstitial cystitis and overactive bladders especially in children or those intolerent to oral administration due to side-effects. The direct effects and mechanism of absorption through the urothelium of these agents is unknown. This study was designed to test the effects of these agents on urothelial permeability and transepithelial resistence (TER).

METHODS: Female Anesthetized New Zealand rabbits were catheterised and instilled with an agent for one hour. The agents studied were saline (control), Oxybutynin (Ditropan Ò 5mg), Tolteradine (Detrol Ò 2mg), Pentosan polysulfate sodium (PPS - Elmiron Ò 100mg) all of which were made up to 20 mls with normal saline and dimethyl sulfoxide (DMSO) (RIMSO-50 Ò 20 mls). The bladder was excised, the muscle dissected free of the urothelium and using an Ussing chamber, water and urea permeability was determined and transepithelial resistance (TER). Results are shown as mean " SEM.

CONCLUSIONS: DMSO is the only intravesical agent used in interstitial cystitis that affects permeability. This suggests that this agent may cause further urothelial damage, and thereby interfers with the inflammatory process of interstitial cystitis. The mechanism of this is unknown but as DMSO is radical scavenger, the penetration of DMSO into the underlying mucosa may inhibit inflammation caused by free radical release. The other agents do not appear to significantly alter the permeability of the urothelium, thus do not appear to have any immediate toxic effect on the urothelium.

Supported by: AFUD; NBF, NIH R37 DK 48217, NIH K12 DK02656

Dr. Burstein's Comment:  This abstract gives one explanation of why DMSO works: it crosses through the bladder lining where it acts as an anti-oxidant and binds up damaging free radicals.


ARE GLOMERULATIONS TYPICAL OF INTERSTITIAL CYSTITIS?

Nagendra Mishra. Ahmedabad, Gujarat, India.

INTRODUCTION AND OBJECTIVES: Glomerulations on cystoscopy are considered to be the hall marks of interstitial cystitis(IC). This prospective study was done in different groups of patients to find out whether glomerulations are present in patients with frequency, urgency and dysuria (fuds)syndrome only or in others too.

METHODS: This study was conducted from JUL. 96 to OCT.99.100 patents were included in the study.60 patients were suffering from chronic fuds syndrome,29 from disease of genitourinary system other than fuds and 11 patients were suffering from some disease other than genitourinary system. Out of 60 patients of fuds group 26 were males and 34 females.Rest 40 had 18 males and 22 females. None of the patients had been recently catheterised or irradiated. None of them had acute urinary tract infection .Cystoscopy was done in all the patients with 21 ch scope, bladder was distended to full capacity under gravity with reservoir height being 80 cms, drained and distended again. 2nd distension was maintained for 3 minutes and bladder drained again. Cold cup biopsy was taken .

RESULTS: Out of 60 patients of fuds syndrome group 30 had glomerulations involving more than 75% area of bladder surface. Rest 30 did not develop glomerulations at all or had only few glomerulation. Most important finding was that the other 40 cases not belonging to fuds syndrome did not develop glomerulations at all even on second distension or hydrodistension.

CONCLUSIONS: This study proves that glomerulations are hall mark of interstitial cystitis. There may be some patients who have similar symptoms of IC but do not develop glomerulations but it is very difficult to find glomerulations in normal persons or persons suffering from other diseases than fuds syndrome.

Supported by: None

Dr. Burstein's Comment:  Glomerulations or pinpoint bladder lining bleeding is still considered the hallmark physical finding in IC.


ANTI-PROLIFERATIVE FACTOR (APF), HEPARIN BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH FACTOR (HB-EGF) AND EPIDERMAL GROWTH FACTOR (EGF) ALTERATIONS IN INTERSTITIAL CYSTITIS (IC) CONFIRMED.

Deborah R. Erickson, Sarah D. Ordille, Chen O. Zhang, Joanna L. Shoenfelt, Susan K. Keay. Hershey, PA; Baltimore, MD.

INTRODUCTION AND OBJECTIVES: Many urine components are reportedly altered in IC, but few have been confirmed by testing a different set of IC patients and controls. One of us (SK) found that the urine specimens from most IC patients had decreased levels of HB-EGF and increased levels of EGF (J Urol 158:1983, 1997), plus a factor (APF) that inhibits growth of cultured bladder epithelial cells (Urol 52:974, 1998). The goal of this study was to confirm these findings.

METHODS: 40 female IC patients and 40 age-matched female controls were recruited by DE to collect 24-hour urine samples. Urine was kept at 4°C during the collection. Aliquots were centrifuged, and supernatants stored at -70°C until assayed by SK, who was blinded to which aliquots were IC or control. Urine APF was measured using a thymidine incorporation assay (Urol 52:974, 1998). HB-EGF and EGF were measured by ELISA (J Urol 158:1983, 1997).

RESULTS: 37 of the 40 IC patients were positive for APF, and one control subject was positive. HB-EGF was decreased and EGF was significantly increased in IC.

CONCLUSIONS: This study confirmed the original findings, using a different group of patients and controls. APF may contribute to epithelial dysfunction in IC, by inhibiting bladder epithelial cell growth. It is currently unknown whether the alterations in EGF and HB-EGF contribute to the pathogenesis of IC, or are responses to bladder epithelial cell injury.

Supported by: Interstitial Cystitis Association (Fishbein Foundation)

Dr. Burstein's Comment:   Anti-proliferative factor is a protein substance in the urine of patients with IC. In laboratory tests, APF inhibits normal bladder cell growth and repair. Whether APF causes IC or is produced in response to the disease is unknown. But this study confirms that it is present only in urine of IC patients and that it may have potential to be used as a marker to diagnose IC.


INTERSTITIAL CYSTITIS OR PROSTATITIS? PENTOSAN POLYSULFATE THERAPY FOR MALE CHRONIC PELVIC PAIN SYNDROME.

Brenda Johnston, Joe Downey, J. Curtis Nickel, the Canadian PPS/CPPS Research Group. Kingston, ON, Canada.

INTRODUCTION AND OBJECTIVES: Chronic pelvic pain syndrome (CPPS) in males may not be a specific prostate problem. CPPS in males has similar clinical and perhaps etiological characteristics as interstitial cystitis (IC). The mechanism of action of pentosan polysulfate (PPS), an oral medication indicated for the treatment of IC, is believed to be supplementation of the glycosoaminoglycans of the bladder surface but there is no data to suggest that PPS reaches or is excreted by the prostate. We undertook an open label multi-center phase II pilot study to examine the potential efficacy of PPS in the treatment of CPPS in males, employing outcome tools validated for chronic pelvic pain syndrome in males.

METHODS: Patients with a diagnosis consistent with NIH CPPS Category IIIA (inflammatory) were treated with PPS, 100 mg tid, for 6 months. Evaluation at baseline, 3 months and 6 months consisted of symptom severity index (SSI), symptom frequency questionnaire (SFQ), a prostatitis pain index (NIH-CPSI), quality of life assessment (QoL) and subjective global assessment (SGA).

RESULTS: 32 Patients (mean age 45.5+/-11 yrs; duration of symptoms 9.2+/-12 yrs) were enrolled in 5 centers. 6 patients withdrew from study. Drug related side effects included hair loss (6%), headache (3%), mild jaundice (3%), mild nausea (3%) and skin flushing (3%).

SGA at 6 months confirmed mild improvement in 30%, moderate in 15% and marked improvement in 15%. 40% of patients had >50% improvement in SFQ; 45% had >50% improvement in SSI, NIH-CPSI and QoL.

CONCLUSIONS: PPS is well tolerated and appears to have efficacy in reducing severity and frequency of general symptoms, reducing specific pain symptoms and improving quality of life in many male patients with CPPS. The safey and efficacy of PPS should be compared to placebo in a well designed randomized controlled trial.

Supported by: ALZA Canada, NIH/NIDDK

Dr. Burstein's Comment: Chronic Prostatitis as defined in this paper has many symptoms in common with IC.  Could it be that it is IC?  It would have been interesting to see the results had these patients undergone hyrodistention to diagnose IC.



SAFETY AND EFFICACY OF 3 DOSES OF PENTOSAN POLYSULFATE (PPS) IN PATIENTS WITH INTERSTITIAL CYSTITIS (IC).

J. Curtis Nickel, Christopher K. Payne, John Forrest, Philip G. Mosbaugh, Jack Barkin. Kingston, ON; Stanford, CA; Tulsa, OK; Indianapolis, IN; Toronto.

INTRODUCTION AND OBJECTIVES: PPS is the only approved oral treatment for relief of bladder pain and discomfort associated with IC. The recommended dose is 300mg/day. We evaluated response and tolerability to 300, 600, and 900mg/day in IC pts.

METHODS: Pts were randomized to 100, 200, or 300 mg tid.The IC Symptom Index (ICSI) and Pts Overall Rating of Improvement of Symptoms (PORIS) were obtained at baseline (BL) 4, 8, 12, 16, 24 and 32 wks of treatment. All pts had BL and follow-up ICSI scores or wk 4 PORIS scores.

RESULTS: At data cutoff (blinded interim analysis) 275 pts enrolled, 137 continued, 76 discontinued. The mean (SD) ICSI scores were 13.0 (3.4) at BL, 11.3 (4.1) at wk 4 and 10.8 (4.7) at wk 12; each score p[<]0.001 v BL.

After 12 weeks, the percent of pts with moderately severe symptom scores (10-16) fell by 42% and the percent of pts with mild to moderate scores (0-9) nearly tripled. Improvement in IC symptom scores was observed as early as 4 wks. The percent of pts who were considered responders (50-100% PORIS score) doubled (18.7% to 39.3%) by wk 12, trend p[<]0.001. No drug-related serious adverse events (AE) were reported. Common AE were diarrhea (18.2%), headache (12.4%), nausea (10.9%), pain (10.9%), and alopecia (3.3%).

CONCLUSIONS: Significant changes in ICSI scores were seen by 4 wks. This study is intended to discern if higher PPS doses increase the rate and extent of IC symptom improvement.

Supported by: ALZA Corporation, Mountain View, California 94039

Dr. Burstein's Comment:   It appears that Elmiron has a definite clinical benefit. This study is still ongoing and has not been unblinded so we still don’t know the results of higher doses. We do know that more side effects have been reported with use of higher doses.


VAGINAL SURFACE ELECTROMYOGRAPHY ANALYSIS IN WOMEN WITH INTERSTITIAL CYSTITIS AND VULVADYNIA TREATED WITH MYOFASCIAL RELEASE.

Rodney U. Anderson, David Wise, Maggie Meadows. Stanford, CA.

INTRODUCTION AND OBJECTIVES: Women suffering from interstitial cystitis and vulvadynia often have painful internal pelvic myofascial trigger points and pelvic floor instability. We report results of monitoring patients with surface vaginal electromyography (EMG) sensors to measure resting microvoltage (mV)as well as contraction ability. Our objective was to determine the usefulness in outcome measurements of myofascial release therapy.

METHODS: Women referred to the Stanford Urology Pelvic Pain Clinic underwent exam, visual analog pain score (VAS), pain questionnaire, and urinary score. Those patients with painful internal pelvic trigger points and surface vaginal pain were measured via vaginal sensor EMG baseline resting tension and contractility. We treated patients with weekly myofascial release massage and ischemic compression of trigger points as well as biofeedback/progressive relaxation training. Visual analog pain score (VAS) and questionnaires served as outcome tools.

RESULTS: There were 43 women evaluated, average age 43 yrs (range 23-85); the working diagnosis was interstitial cystitis in 21 (49%) and vulvadynia in 22 (51%). The women underwent a median of 10 myofascial treatments over two months.                                                                         

CONCLUSIONS: Internal myofascial release therapy represents a complementary physical therapy for those women suffering from chronic pelvic pain syndromes such as interstitial cystitis and vulvadynia. Vulvadynia patients tend to have adequate relaxation of the pelvic floor, but show hypocontractility and poor localization of voluntary muscle control. Myofascial release and biofeedback help them to improve this performance.

Dr. Burstein's Comment: Notice that this involves internal therapy done at a pain referral center. Pelvic floor instability can occur secondary to numerous disorders of the pelvis including vulvadynia and IC .  It is refreshing to see the significant results from this complimentary approach.


PERCUTANEOUS S3 NERVE ROOT NEUROSTIMULATION DECREASES SYMPTOMS AND NORMALIZES URINARY HB-EGF AND APF ACTIVITY IN IC PATIENTS.

Toby C. Chai, Chen-Ou Zhang, John W. Warren, Susan K. Keay. Baltimore, MD.

INTRODUCTION AND OBJECTIVES: Interstitial cystitis (IC) has been associated with the presence of an urinary anti-proliferative factor (APF) and decreased urinary heparin-binding epidermal growth factor like growth factor (HB-EGF) concentration. S3 nerve root neurostimulation has been approved to treat urinary urgency and frequency syndrome and is being evaluated as a treatment for IC. We therefore explored whether symptoms and objective measures of urinary HB-EGF and APF activity changed in IC patients after percutaneous S3 neurostimulation (PNS).

METHODS: Six patients (mean age 49, 5 females, 1 male) who fulfilled NIDDK criteria for IC consented to PNS which was performed in the office as an outpatient procedure under local anesthetic. Voiding frequencies, urine specimens, and pelvic pain/urinary urgency scores (from a Likert scale of 1-10) were obtained both prior to PNS and following 5 days of continuous PNS. Urine specimens were measured for HB-EGF concentration and APF activity as previously described.

RESULTS: PNS significantly changed all measured parameters compared to pre-PNS.

CONCLUSIONS: S3 PNS significantly decreased symptoms and normalized urinary HB-EGF and APF activity in IC patients. Based on these preliminary data, additional studies may be warranted to determine whether placement of a permanent impulse generator for S3 neuromodulation is an effective form of therapy for IC.

Supported by: PNS kits supplied by Medtronics Inc., Minneapolis, MN

Dr. Burstein's Comment:  Important Notice! There were only 6 patients enrolled in this study. Such a small number cannot be used to propose or recommend PCN as an effective treatment for IC. The results may look promising, certainly further evaluation is needed.  This study also confirms anti-proliferative factor activity and its response to neuromodulation and symptom relief. APF  has become a very exciting area of IC research.



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