BJU International EFFECTS OF INTRAVESICAL HYALURONIC ACID/CHONDROITINE SULFATE IN PATIENTS WITH INTERSTITIAL CYSTITIS/PAINFUL BLADDER SYNDROME

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1 EFFECTS OF INTRAVESICAL HYALURONIC ACID/CHONDROITINE SULFATE IN PATIENTS WITH INTERSTITIAL CYSTITIS/PAINFUL BLADDER SYNDROME Journal: Manuscript ID: Manuscript Type: Date Submitted by the Author: BJU Original Article 21-Dec-2007 Complete List of Authors: Porru, Daniele; Policlinico S. Matteo, Divisione Urologia Cervigni, Mauro; S. Carlo-IDI Hospital, Urogynecology Unit Nasta, Loredana; AICI Interstitial Cystitis Italian Association Natale, Franca; S. Carlo-IDI Hospital, Urogynecology Unit Gardella, Barbara; Fondazione IRCCS Policlinico S. Matteo, Gynecology Department Lo Voi, Roberto; S. Carlo-IDI Hospital, Urogynecology Unit Spinillo, Arsenio; Fondazione IRCCS Policlinico S. Matteo, Gynecology Department Rovereto, Bruno; Fondazione IRRCS Policlinico S. Matteo, Divisione Urologia keywords: Abstract: Interstitial cystitis/painful bladder syndrome, Hyaluronic acid, Chondroitine sulfate, Intravesical treatment Objectives- The aim of our study was to evaluate the effect of a more viscous compound than existent hyaluronic acid formulation, in helping to restore a defective glycosaminoglycan layer, and therefore in improving Interstitial Cystitis//Painful Bladder Syndrome (IC/PBS) symptoms when administered intravesically in IC/PBS patients. Methods- A total of 23 female patients completed the study. The patients received endovesical administration of hyaluronic acid and chondroitin sulfate in normal saline, 40 ml, weekly for 12 weeks and then be-weekly for 6 months, if there was initial response. Results- Interstitial Cystitis Symptom and Problem Index (ICSI/ICPI) and Pelvic Pain and Urgency/Frequency Symptom Scale (PUF) showed a significant improvement after 12 weeks, which was maintained thereafter. The average number of voidings and mean voiding volumes revealed significant improvement after the 12 weeks' treatment period, with a significant reduction and increase, respectively. Mean voiding volume increased from 143 ml to 191 ml, which apparently was not reflected in a corresponding reduction of number of daily voids (from 15,5 to 14).

2 Page 1 of 20 VAS values decreased from 5,4 to 3,6 (pain) and from 6,0 to 3,5 (urgency) after the period of treatment, showing a significant improvement. Two patients had to stop weekly intravesical treatment due to urinary tract infections observed after catheterization, and two additional patients had to stop maintenance be-weekly home selfadministration after the 12 weeks course. Conclusions- In our preliminary experience, intravesical hyaluronic acid plus chondroitine sulphate appears to be a safe and efficacious method of treatment in IC/PBS.

3 Page 2 of 20 1 EFFECTS OF INTRAVESICAL HYALURONIC ACID/CHONDROITINE SULFATE IN PATIENTS WITH INTERSTITIAL CYSTITIS/PAINFUL BLADDER SYNDROME Daniele Porru, Mauro Cervigni*, Loredana. Nasta, Franca Natale*, Barbara Gardella **, Roberto Lo Voi*, Arsenio Spinillo**. and Bruno Rovereto. Urology Department, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy. * Uro-Gynecological Dept., San Carlo-IDI Hospital, Rome, Italy. President of AICI (Interstitial Cystitis Italian Association) ** Clinica Ostetrica e Ginecologica, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy. Corresponding author: DANIELE PORRU MD, Divisione Urologia Fondazione IRCCS Policlinico San Matteo, Viale Golgi 2, Pavia 27100, Italy. Tel+39/0382/ ; fax: +39/0382/503403; danieleporru@tin.it. Source of funding: The Company IBSA-Switzerland provided the product for all patients and sponsored the study. We thank Dr. Alessio Anghileri and Matteo Provini, for producing the graphical illustrations. Keywords: Interstitial cystitis/painful bladder syndrome, Hyaluronic acid, Chondroitine sulfate, Intravesical treatment.

4 Page 3 of 20 2 ABSTRACT Objectives- The aim of our study was to evaluate the effect of a more viscous compound than existent hyaluronic acid formulation, in helping to restore a defective glycosaminoglycan layer, and therefore in improving Interstitial Cystitis//Painful Bladder Syndrome (IC/PBS) symptoms when administered intravesically in IC/PBS patients. Methods- A total of 23 female patients completed the study. The patients received endovesical administration of hyaluronic acid and chondroitin sulfate in normal saline, 40 ml, weekly for 12 weeks and then be-weekly for 6 months, if there was initial response. Results- Interstitial Cystitis Symptom and Problem Index (ICSI/ICPI) and Pelvic Pain and Urgency/Frequency Symptom Scale (PUF) showed a significant improvement after 12 weeks, which was maintained thereafter. The average number of voidings and mean voiding volumes revealed significant improvement after the 12 weeks treatment period, with a significant reduction and increase, respectively. Mean voiding volume increased from 143 ml to 191 ml, which apparently was not reflected in a corresponding reduction of number of daily voids (from 15,5 to 14). VAS values decreased from 5,4 to 3,6 (pain) and from 6,0 to 3,5 (urgency) after the period of treatment, showing a significant improvement. Two patients had to stop weekly intravesical treatment due to urinary tract infections observed after catheterization, and two additional patients had to stop maintenance be-weekly home self-administration after the 12 weeks course. Conclusions- In our preliminary experience, intravesical hyaluronic acid plus chondroitine sulphate appears to be a safe and efficacious method of treatment in IC/PBS.

5 Page 4 of 20 3 INTRODUCTION Interstitial cystitis/painful bladder syndrome (IC/PBS) is a treatable but, so far, essentially incurable debilitating clinical syndrome, diagnosed more frequently in women, and manifested by chronic pelvic pain and urinary frequency occurring in the absence of any known etiology (1). Its cardinal symptoms - pain on bladder filling (relieved by emptying) and urinary frequency - are, in reality, an exaggeration of the normal perceptions of discomfort prompting urination that all persons experience. Although IC/PBS has been recognized for more then a century, its cause remains largely obscure. However, a multitude of pathophysiologic mechanisms have been suggested. Hyaluronic acid (HA) is a natural proteoglycan that is hypothesized to replenish a defective glycosaminoglycan layer in IC/PBS patients upon intravesical application. Initially, Morales (2) treated 25 patients and reported a 56% (week four) and 71% (week seven) response rate. Beyond week 24 effectiveness decreased but there was no significant toxicity. More recently, Nordling (3) reported a 3-year follow-up to a 3-month prospective, nonrandomized study evaluating the effect of intravesical hyaluronic acid on IC/PBS symptoms. According to this report, 11 of the initially included 20 patients chose to continue treatment beyond the initial trial and modest beneficial long-term effects were noted in about two thirds of patients. To further investigate the effects of hyaluronate, Boucher et al. (4) studied its impact on bladder mast cells and the release of proinflammatory mediators in rat urine. In this study, a stress-provoked mast cell activation and the secretion of proinflammatory mediators could be inhibited by sodium hyaluronate. We assumed that a more viscous compound than existent HA formulation, such as the one used, would be more effective in helping to restore a defective glycosaminoglycan layer.

6 Page 5 of 20 4 Besides, a solution consisting in a combination of HA and chondroitin sulphate, which had already been used as a single agent in IC/PBS patients (5), could produce additional benefits in patients than the use of its single components. PATIENTS AND METHODS Hyaluronic acid, also called sodium hyaluronate, was obtained in vials containing 40 ml of a clear, sterile, nonpyrogenic preparation of a high molecular weight fraction of sodium hyaluronate 1.6 % p/v associated with chondroitin sulfate 2.0 % p/v. Twenty-seven women 20 to 65 years old (mean 46.68, SD 13.63), with symptoms characteristic of Interstitial Cystitis/Painful Bladder Syndrome according to the criteria established by the National Institute of Health Consensus Conference (6) entered the trial, being recruited in two Centers. The study received institutional approval and the patients signed a written informed consent form explaining the investigational nature of the treatment plan. Inclusion criteria were as follows: 1. pain on bladder filling which improved after micturition 2. suprapubic, pelvic, urethral, vaginal or perineal pain 3. presence of glomerulations during hydrodistension Exclusion criteria were as follows: 1. pregnancy 2. age less than 18 years 3. history of bladder tumours 4. radiation cystitis

7 Page 6 of vaginitis 6. symptomatic bladder or urethral diverticulum 7. active genital herpes 8. bladder or urethral stones 9. voiding frequency less than 10 times a day 10. symptoms present for less than 6 months After bladder catheterization with a sterile Nelaton catheter 10 or 12 Ch, the bladder was emptied, and the patients received endovesical administration of hyaluronic acid and chondroitin sulfate in normal saline, 40 ml, weekly for 12 weeks and then be-weekly for 6 months, if there was initial response; a single dose of oral antibiotic was administered before catheterization. The solution was maintained for 1 hour before voiding. The primary endpoint of our trial was to evaluate the efficacy of a therapeutic regimen consisting in weekly intravesical instillations of sodium hyaluronate 1.6 p/v with chondroitin sulfate 2.0 % 1.6 p/v, for a period of 12 weeks, in female patients with a diagnosis of IC/PBS: To this aim, assessment of urgency and pain by means of VAS (10 cm), reduction of number of voiding by means of voiding diary, and O Leary-Sant IC Symptom and Problem Index (7), and PUF questionnaire (8) were used. The self-administered O Leary-Sant IC symptom and problem index (ICSI/ICPI) has eight questions assessing pain and voiding symptoms. The maximal index score of 36 reflects maximal symptom and problem severity; the lowest possible score is 0. Outcomes were evaluated at baseline and 3 and 6 months after initiation of therapy. Results were evaluated by comparing pre and post-treatment values of the following tests:

8 Page 7 of days voiding diary, O Leary-Sant Symptom score, PUF questionnaire; VAS for urgency and pain. The following investigations were performed before inclusion: KCl sensitivity test as described by Parsons (6), cystoscopy, hydrodistension and bladder biopsy performed under sedation or spinal anaestesia; urodynamic examination was available in 12 patients. The baseline values were compared to 12-week assessment and 6 months assessment. The statistical analysis was performed using the T-test for independent variables. We considered statistically significant p< RESULTS A total of 23 female patients completed the study. Baseline patient characteristics are reported in Table 1, more than 91% reported having symptoms for more than 1 year. Mean follow-up was 5 months, range 3 to 8 months. No patient had intolerance and/or side effects related to treatment. There were 69% who presented with moderate/severe pain and 69% with moderate/severe urgency, defined as a score of 5 or greater on the 0 to 10 VAS scale. Baseline mean 24-hour voiding frequency as recorded on the voiding diaries was 15.5 per day (SD: 7.4). Average voided volume was ml (SD: 56.8). Baseline values for the composite symptom scores and patients clinical data are shown in Table 2. Most patients were on concomitant oral therapies to relieve their bothersome symptoms. The data from the analysis of the questionnaires at baseline and after 12 weeks treatment are reported in Table 3 and 4. Both Interstitial Cystitis Symptom and Problem Index and Pelvic Pain and Urgency/Frequency Symptom Scale (PUF) showed a mean significant improvement after 12 weeks of treatment, which was maintained thereafter (Table 5), although only data from ICSI/ICPI and PUF are available at 6 months.

9 Page 8 of 20 7 The average number of voidings and mean voiding volumes revealed significant improvement after the 12 weeks treatment period, with a significant reduction and increase, respectively (Fig. 1-2); mean voiding volume increased significantly, from 143 ml to 191, which apparently was not reflected in a corresponding reduction of number of daily voids (from 15,5 to 14). The analysis of the VAS showed the data reported in Table 6. VAS values were 3,6 (pain) and 3,5 (urgency) after the cycle of treatment, being initially 5,4 and 6.0, respectively; the improvement was statistically significant. Two patients had to stop weekly intravesical treatment due to urinary tract infections observed after catheterization, and two additional patients had to stop maintenance be-weekly home self-administration of the product after completing 12 weeks intravesical treatment, due to bacterial urinary tract infections. DISCUSSION Hyaluronic acid is a natural proteoglycan that is hypothesized to replenish a defective glycosaminoglycan layer in IC/PBS patients (9, 10) upon intravesical application. Initially, Morales (2) treated 25 patients and reported a 56% (week four) and 71% (week seven) positive response rate. Beyond week 24 effectiveness decreased, with no significant toxicity. Nordling (3) reported a 3-year follow-up in a 3-month prospective, nonrandomized study; 11 of the initially included 20 patients chose to continue treatment beyond the initial trial, and modest beneficial long-term effects were noted in two thirds of IC/PBS patients. Besides, Boucher et al (4) studied the impact of H.A. on bladder mast cells and the release of proinflammatory mediators could be inhibited by sodium hyaluronate. A lower success rate was reported subsequently in a small group of IC/PBS patients in a non-randomized trial

10 Page 9 of 20 8 (11). For this reason, several authors suggest investigating hyaluronic acid treatment particularly in IC/PBS patients with bladder mastocytosis and stress-related exacerbation. The possibility that the fundamental role of H.A. is mainly the reconstitution of a morphologically defective glycosaminoglycan layer may not be true. The compound exhibits various biological activities which may explain its effect in IC/PBS, such as the adherence inhibition of immune complexes to polymorphonuclear cells, inhibition of leucocyte migration and aggregation due to viscosity (12), and regulation of fibroblast and endothelial cell proliferation (13, 14). Numerous drugs have been proposed to treat IC/PBS by intravesical administration, but their use is limited by lack of efficacy, prolonged time to achieve a therapeutical response, and short duration of response (15). Chondroitin sulfate solution 2.0% is a glycosaminoglycan (GAG) replenishment therapy, which was instilled into the bladder of GAG-deficient patients with IC/PBS. Two nonrandomized, uncontrolled pilot studies report improvements in patient-reported symptoms after the use of chondroitin sulfate for one year (5). We supposed that a more dense and viscous solution of hyaluronic acid could produce more long-lasting improvement on symptoms of this condition. Besides, calcium chondroitine was contained in the solution for intravesical administration. CONCLUSION In our preliminary experience, the administration of intravesical hyaluronic acid plus chondroitine sulphate appears to be a safe and efficacious method of treatment in IC/PBS. In responsive patients, the effect appeared to persist during maintenance treatment and followup visits, consisting in an improvement of both urgency-frequency related symptoms and

11 Page 10 of 20 9 bladder/pelvic pain. No significant side effects were recorded, and concomitant oral therapies could be continued. In order to confirm these initial encouraging results, further controlled, randomized studies are necessary with greater number of patients and a longer follow-up. REFERENCES 1) Hanno P: Interstitial Cystitis and Related Disorders. In: Walsh P, ed. Campbell's Urology. 8th ed. Philadelphia: Elsevier; 2002: 631,. 2) Morales A, Emerson L, Curtis NJ et al: Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol 1996: 156: ) Nordling J, Jorgensen S and E Kallestrup: Cystistat for the treatment of interstitial cystitis: a 3-year follow-up study. Urology 2001: 57 (6 Suppl 1). 4) Boucher WS, Letourneau R, Huang M et al: Intravesical sodium hyaluronate inhibits the rat urinary mast cell mediator increase triggered by acute immobilization stress. J Urol 2002: 167: ) Palylyk-Colwell E: Chondroitin sulphate for interstitial cystitis. Issues Emerg health technol 2006: 86: ) Gillenwater JY and Wein AJ: Summary of the National Institute of Arthritis, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, J Urol 1988: 140: ) Bernie JE, Hagey S, Albo ME, et al: The intravesical potassium sensitivity test and urodynamics: implications in a large cohort of patients with lower urinary tract symptoms. J Urol. 2001: Jul 166(1): ) O Leary MP, Sant GR, Fowler FJ et al: The Interstitial Cystitis Symptom Index and Problem Index. Urology 1997: 49 (suppl 5A):

12 Page 11 of ) Minaglia S, Ozel B, Nguyen JN et al: Validation of Spanish version of Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale. Urology 2005: 65(4): ) Oberpenning F, van Ophoven A, Hertle L: Interstitial cystitis: an Update. Curr Opin in Urology 2002: 12 (4): ) Porru D, Campus G, Tudino D et al : Results of treatment of refractory interstitial cystitis with intravesical hyaluronic acid. Urol Int 1997: 59: ) Iavazzo C, Athanasiou S, Pitsouni E et al: Hyaluronic Acid: an effective alternative treatment of interstitial cystitis, recurrent urinary tract infections, and hemorrhagic cystitis. Eur Urol. 2007: 51(6): ) Balasz EA and Denlinger JL: The role of hyaluronic acid in arthritis and its therapeutic use. In: Osteoarthritis: Current Clinical and Fundamental Problems. Edited by JG Peyron. Basel: Geigy, 1984: ) Hanno: Interstitial cystitis and related diseases. In: Campbell s Urology, 7 th ed. Edited by PC Walsh, AB Retik, ED Vaughan Jr and AJ Wein. Philadelphia: WB Saunders, Co,, vol.1,sect IV, chapt 17: 1998: ) Goldberg RL and Toole BP: Hyaluronate inhibition of cell proliferation. Arth Rheum 1987: 30: 769.

13 Page 12 of TABLE 1. Baseline patient characteristics. No. subjects: 23 No. with symptoms more than 52 wks (%): 21 (91,3) Mean age at study entry ± SD: 46.5 (13.6) Mean 24-hr frequency ± SD: 15.5 (7.4) Mean av 24-hr voided vol (cc) ± SD* (56.8) KCl test positive 14/23 Mean pain score ± SD (0 9) 5.4 (2.8) Mean urgency score ±SD (0 9) 6.0 (2.3) Mean O Leary-Sant IC Symptom Index (0 20) ± SD 13.1 (2.3) Mean O Leary-Sant IC Problem Index (0 16) ± SD 12.7 (2.2) Mean PUF (0 42) ±SD 22.3 (5.2) Bladder capacity ± SD (228) Average of 2 baseline scores.

14 Page 13 of Table 2: Baseline data of IC /PBS patients in the HA treatment group. Pt A H (cm) W(Kg) S D C S M BC Gl KCl Test O L PUF VAS- P VAS- U 1 TM N 600 Y Pos ,8 4, PS N 800 Y Pos CS N 600 Y Neg RC N 660 Y Pos ,9 6, R Ca Y 380 Y Neg ,2 8, CM N 600 Y Pos , DV N 650 Y Pos ,9 5, VR Y 500 Y Neg MS N 750 Y Neg , CanM N 600 Y Pos ,3 6, BA Y 700 Y Neg ,2 6, PV Y 500 Y Neg ,5 5, BB N 1000 Y Pos RP Y 1000 Y Pos OA Y 950 Y Pos SM Y 360 Y Pos , GM Y 650 Y Neg TE Y 700 Y Neg B.RS N 600 Y Pos MP Y 150 Y Pos LG Y 400 N Pos RG Y 500 N Neg , PA Y 110 Y Pos , NM AV

15 Page 14 of Legenda: Pt= patient Gl= glomerulations A= age KCl Test= Potassium sensitivity test H= height O L= O Leary-Sant Symptom Score W= weight PUF= Pain Urgency Frequency Questionnaire SD= spontaneous delivery VAS-P= Pain visual analog scale CS= cesarean section VAS-U= Urgency visual analog scale M= menopause BC= Bladder capacity under sedation/spinal anesthesia NM= number of micturitions AV= average volume of micturition

16 Page 15 of Tab.3 O Leary-Sant Interstitial Cystitis Symptom and Problem Index Symptoms 8-20 (mean 13,9 SD 3,7) Problems 7-16 (mean 11.5 SD 2,2) Total (mean SD 4,81) Pre-treatment Post-treatment P 6-20 (mean 11,22 SD 3,8) 4-16 (mean 10,13 SD 3,14) (mean SD 6,70) 0.004* 0.01* *

17 Page 16 of Tab. 4 Pelvic Pain and Urgency/Frequency Symptom Scale Pre-treatment Post-treatment P Symptom 8-19 (mean SD 3,35) Bother 2-21 (media 8,57 SD 3,55) Total (mean 22,30 SD 5,20) 3-25 (mean SD 4,60) 2-12 (mean 6,04 SD 2,85) 6-31 (mean 17,40 SD 6,20) 0.001* 0.003* *

18 Page 17 of Table 5 Changes in symptoms from baseline to 3-months and 6-month follow-up Mean ± SD Baseline End of Treatment 6 Mo Follow-up ICSI/ICPI score sum: 25.8 ± ± ± 5.2 Pain (mm on VAS): 5.4 ± ± 2.5 _ Urgency (mm on VAS): 6.0 ± ± 1.7 _ 24-Hr frequency: 15.5 ± ± 7.6 _ Bladder vol (ml): ± ± 96.4 _ PUF 22.3 ± ± ± 4.8

19 Page 18 of Fig.1 Number of voidings at baseline and at 12 weeks. n voids/day ,52 13, Pre-treatment Post-treatment

20 Page 19 of Fig.2 Average voided volume at baseline and at 12 weeks. 191,26 mean urine volume/void ,13 0 Baseline 12 weeks

21 Page 20 of Tab. 6 VAS for pain, frequency and urgency at baseline at 12 weeks. Pre-treatment Post-treatment P Pain 1-9 mean 5,4 (SD 2.8) Urgency 1-10 mean 6,0 (SD 2.3) 0-9 mean 3,6 (SD 2.5) 1-8 mean 3,5 (SD 1.7) * *

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