CYCLOSPORINE A AND PENTOSAN POLYSULFATE SODIUM FOR THETREATMENT OF INTERSTITIAL CYSTITIS: A RANDOMIZED

COMPARATIVE STUDY

JUKKA SAIRANEN,* TEUVO L. J. TAMMELA, MIKAEL LEPPILAHTI, MARKKU MULTANEN,ILKKA PAANANEN, KARI LEHTORANTA AND MIRJA RUUTU

From the Department of Urology, Helsinki University Hospital, Helsinki (JS, MR), Department of Surgery/Urology, Tampere UniversityHospital and Medical School, Tampere (TLJT), Division of Urology, Seinajoki Central Hospital, Seinajoki (ML), Department of

Surgery, Kuusankoski District Hospital, Kuusankoski (MM), Department of Urology, Oulu University Hospital, Oulu (IP),and Department of Surgery, Paijat-Hame Central Hospital, Lahti (KL), Finland

ABSTRACT

Purpose: In a previous retrospective analysis, cyclosporine A (CyA) was highly efficient intreating patients with interstitial cystitis. A prospective randomized study with this immuno-suppressive agent was warranted. We compared CyA to pentosan polysulfate sodium (PPS) inpatients with interstitial cystitis.

Materials and Methods: A total of 64 patients with interstitial cystitis meeting the NationalInstitute of Diabetes and Digestive and Kidney Diseases criteria were enrolled in a randomizedprospective study. Patients were randomized in a 1:1 ratio to 1.5 mg/kg CyA twice daily (27women, 5 men) or 100 mg PPS 3 times daily (26 women, 6 men) for a period of 6 months. Theprimary end point was daily micturition frequency, and secondary end points were mean andmaximal voided volume, number of nocturia episodes, O’Leary-Sant symptom and problemindexes, visual analogue scale for pain, and subjective global response assessment.

Results: CyA was superior to PPS in all clinical outcome parameters measured at 6 months.Micturition frequency in 24 hours was significantly reduced in the CyA arm compared to the PPSarm (-6.7 � 4.7 vs -2.0 � 5.1 times). The clinical response rate (according to global responseassessment) was 75% for CyA compared to 19% for PPS (p �0.001). Although there were moreadverse events in the CyA arm than in the PPS arm, 29 patients completed the 6-month followupin both groups.

Conclusions: CyA is more effective than PPS in interstitial cystitis.KEY WORDS: cystitis, interstitial; cyclosporine, pentosan sulfuric polyester, drug therapy

Interstitial cystitis (IC) is a debilitating inflammatorybladder disease characterized by urinary symptoms. Symp-toms include urinary urgency, frequency, nocturia, and su-prapubic or pelvic pain without any known etiological factor.Thus, there is no target for specific treatment. The NationalInstitute of Diabetes and Digestive and Kidney Diseases(NIDDK) has established diagnostic criteria to standardizethe diagnosis of IC based on patient symptoms and cysto-scopic findings with the patient under anesthesia.1 Stan-dardized criteria make it possible to compare clinical studieson IC. Multiple treatments have been recorded in the ICdatabase.2 Previous placebo controlled trials of oral pentosanpolysulfate sodium (PPS) on IC have shown varying degreesof efficacy.3�5 However, the limited efficacy of PPS is consid-ered to be higher than the effect of placebo. By using the dataavailable, the Food and Drug Administration has approvedPPS when indicated in treating patients with IC.

The long-term experience with cyclosporine A (CyA) ofpatients with severe IC showed that CyA treatment waseffective and well tolerated.6 However, retrospective analysiswarranted a randomized prospective trial. In the presentstudy we compared CyA with PPS. Followup of 6 months was

selected because in that time the clinical effect of the studydrugs would be clear. Because both arms of the study had anactive drug it was also motivating for patients to enter thestudy. We tested the efficacy of CyA in comparison to PPS ina randomized open label prospective multicenter study.

MATERIALS AND METHODS

A total of 64 patients meeting the NIDDK criteria of inter-stitial cystitis were randomized in a1:1 ratio to cyclosporineA (Sandimmun Neoral®) or to pentosan polysulfate sodium(bene-Arzneimittel GmbH, Munich, Germany) treatment for6 months. The cyclosporine A dose was 3 mg/kg divided into2 daily doses, while that of PPS was 100 mg 3 times daily.The first patient was randomized in October 2002 afterwhich enrollment of the 64 patients lasted for 17 months.Seven Finnish urological units participated in this study (seeAppendix). Exclusion criteria for the study were history ofcancer in the last 10 years, untreated hypertension or renalinsufficiency (serum creatinine greater than normal limits of90 mg/dl in females or 100 mg/dl in males). As CyA may causeliver dysfunction or hypercholesterolemia, serum transami-nases, bilirubin and serum cholesterol had to be within nor-mal range. All patients underwent urodynamic studies torule out detrusor overactivity. If the urodynamic study wasdone within the last 2 years and no change in clinical symp-toms occurred suggestive of other disease than IC, it was notobligatory to redo it. The study protocol was approved by theEthical Committee of Helsinki University Hospital.

Submitted for publication February 16, 2005.Study received Helsinki University Hospital Ethical Committee

approval.Supported by a grant from the Finnish Urological Association.* Correspondence: Department of Urology, Maria Hospital, PL

580, 00029 HUS, Helsinki, Finland (telephone: �358504271039;FAX: �358947163387; e-mail: jukka.sairanen@hus.fi).

For another article on a related topic see page 2382.

0022-5347/05/1746-2235/0 Vol. 174, 2235–2238, December 2005THE JOURNAL OF UROLOGY® Printed in U.S.A.Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1097/01.ju.0000181808.45786.84

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All patients gave written informed consent. No other treat-ments for IC were accepted during the study. If the patientswere using nonsteroidal anti-inflammatory drugs or otherpainkillers or medication for insomnia when entering thestudy, they were allowed to continue the treatment. Random-ization was centralized. Closed envelopes were divided into 2identical blocks, and a nurse not otherwise involved in thestudy opened the envelopes containing the name of the drug.

Baseline voiding symptoms were recorded in 2-day voidingdiaries, visual analogue scale (VAS) for worst pain, andO’Leary-Sant symptom and problem indexes for IC.7 Controlvisits were at 1, 3 and 6 months. At the visits patientsreturned 2-day voiding diaries, marked the VAS score, filledout symptom and problem questionnaires, and gave theglobal response assessment (GRA). GRA was defined as1—worse, 2—no change, 3—slightly better, 4—moderatelybetter, 5—much better and 6—completely cured. Partici-pants who reported categories 4 to 6 were considered treat-ment responders.

Due to possible nephrotoxicity and development of hyper-tension in CyA group, serum creatinine and blood pressurewere controlled monthly. If blood pressure or serum creati-nine exceeded the normal limits, the CyA dose was reduced tohalf. Also, in case of subjective intolerable side effects, it waspossible to reduce the CyA dose. In all visits urinalysis wasperformed to rule out bacterial infection.

The primary end point of the study was micturition fre-quency in 24 hours. Secondary end points were maximalbladder capacity, mean voided volume, number of nocturiaepisodes, O’Leary-Sant symptom and problem scores, VASscore, and GRA. A sample size of 64 patients was selected todetect a difference in response rates of 70% and 35%. Ourhypothesis was that in 70% of patients with IC, micturitionfrequency in 24 hours is reduced to half when on CyA treat-ment, and the same effect would be seen in 35% of patients onPPS. Power of 80% at a 2-sided significance level of 5% wasused. Loss of 10% of patients in both groups was estimated.Baseline factors were compared with the t test and theMann-Whitney rank sum test, and differences between treat-ment outcomes were calculated with the Mann-Whitney ranksum test. Proportions of responders were calculated with theFisher exact test with p �0.05 considered significant. TheWilcoxon signed rank test was used in calculating differencesin blood pressure changes during CyA treatment. Statisticalanalysis was performed with Jandel SigmaStat® statisticalsoftware.

RESULTS

The recruitment of patients was effective and the plannednumber of patients was achieved in a reasonable time. Eachcenter enrolled between 1 and 21 patients. Baseline patientcharacteristics are presented in table 1. The patients did notdiffer in any of the baseline parameters.

Hunner’s ulcer was seen on cystoscopy in 15 of 64 patients,with 5 patients with Hunner’s ulcer in the CyA group and 10in the PPS group. Median bladder capacity in all patientsunder anesthesia was 500 ml (range 250 to 1,330). Previoustreatments for IC were as usual in both groups. In bothgroups 12 patients had had repeated hydrodistention. Therewere 18 patients in the CyA group and 17 patients in the PPSgroup in whom at least 3 different treatments had previouslyfailed. In the CyA group 16 patients had received intravesicaldimethyl sulfoxide, 8 had received intravesical hyaluronateand 5 had intravesical bacillus Calmette-Guerin previously.In the PPS group 15 patients had received intravesical di-methyl sulfoxide, 10 had intravesical hyaluronate and 6 hadintravesical bacillus Calmette-Guerin. In individual caseshydroxyzine, cimetidine, oxychloroquine, antipsychotics,�-blockers, transcutaneous neurostimulation and urethralHegar dilations had also been tried. In both groups 8 patients

had been on antimuscarinics. There were 5 patients in theCyA group and 4 patients in the PPS group who had receivedtramadol (50 to 250 mg) as a painkiller when entering thestudy. None received strong opioids.

A total of 29 patients completed the study in both groups.In the PPS arm the reason for withdrawal was gross hema-turia in 1 patient after 2 months, while 2 other patientsdiscontinued the study at 1 and 3 months as they did notbenefit from treatment. In the CyA arm all 3 withdrawalsoccurred within 1 month. The reasons for discontinuationwere multiple adverse events in 1 patient (headache, pares-thesia in palms of the hands and gingival hyperplasia), gas-trointestinal pain and gingival hyperplasia in another, whilethe third patient dropped out due to emesis after just 5 daysof treatment.

The primary end point of this study was the reduction byhalf of micturition frequency in 24 hours. This effect was seenin 11 patients (34%) in the CyA group and in no patients (0%)in PPS group (p �0.001). CyA was also significantly moreeffective than PPS in all other objective and subjective pa-rameters measured. Number of nocturia episodes, O’Leary-Sant symptom score, IC symptom index and problem index,as well as VAS score decreased while maximal bladder ca-pacity and mean voided volume increased significantly morein patients treated with CyA (table 2).

The proportion of responders (GRA category 4 to 6) in theCyA group increased at every visit while in the PPS group itremained the same, so that CyA was significantly superior toPPS from the 3-month visit (table 3). In the CyA group thenumber of responders at 6 months was significantly higher

TABLE 1. Baseline patient characteristics by treatment group

Mean � SD

Cyclosporine APentosan

PolysulfateSodium

Pt age 56.2 � 14.7 59.7 � 13.0Yrs symptoms 7.8 � 7.0 8.9 � 6.7Cystometric capacity (ml) 232 � 99 201 � 99Frequency in 24 hrs 16.7 � 4.4 19.1 � 8.4Nocturia episodes 3.9 � 2.2 4.2 � 3.3Max bladder capacity awake

(ml)230 � 81 189 � 78

Mean voided vol (ml) 122 � 39 106 � 46O’Leary-Sant symptom score

(range 0–36)29.4 � 4.8 30.2 � 3.7

IC symptom index (0–20) 15.7 � 2.8 16.6 � 2.0IC problem index (0–16) 14.0 � 1.7 14.0 � 1.8Visual analogue scale VAS

(0–10 cm)6.8 � 2.0 7.0 � 2.1

There were no statistically significant differences in baseline parametersbetween the 2 groups.

TABLE 2. Changes in parameters after 6 months treatment

Mean � SD

Cyclosporine APentosan

PolysulfateSodium

p Value

Frequency in 24 hrs �6.7 � 4.7 �2.0 � 5.1 �0.001Max bladder capacity awake

(ml)81 � 94 2.8 � 60 0.003

Mean voided vol (ml) 59 � 57 1 � 31 �0.001Nocturia episodes �2.2 � 1.6 �0.2 � 2.1 �0.001O’Leary-Sant symptom score

sum�15.0 � 9.4 �3.1 � 4.3 �0.001

IC symptom index �7.9 � 4.6 �2.0 � 2.6 �0.001IC problem index �7.1 � 4.4 �1.5 � 1.8 �0.001VAS (cm) �4.7 � 3.5 �1.6 � 3.3 �0.001

CYCLOSPORINE A AND PENTOSAN POLYSULFATE SODIUM FOR INTERSTITIAL CYSTITIS2236

than after 1 month (24 of 32 vs 13 of 32, p � 0.006). Amongresponders 19 of 32 (59%) in the CyA arm reported GRA score5 (much better) or 6 (completely cured) compared with 4 of 32(13%, p �0.001) in the PPS arm. A post-hoc analysis showeda difference in patient age between patients responding verywell (GRA 5 or 6) and those with slight response or noresponse at all (GRA 1 to 4). Patients achieving the besttherapeutic effect with CyA had a higher mean age (59.6[14.6] vs 47.2 [12.1] years, p � 0.03).

None of the responders had taken any additional painmedication compared to their medication at baseline. On thecontrary all 5 patients in the CyA group could eliminate theirdaily tramadol as the symptoms alleviated. There were nostatistically significant changes in mean systolic or diastolicblood pressure or serum creatinine during the 6-month treat-ment with CyA (table 4.) In no patients was new treatmentfor hypertension started. However, in 2 patients the initialCyA dose was decreased to half because of increased diastolicblood pressure, which was regarded as clinically significant.Blood pressure normalized after CyA dose reduction. Serumcreatinine remained within normal limits in all but 1 patient.In 1 patient serum creatinine increased from the baselinevalue of 65 (range 50 to 90) to 102 mg/dl at 3 months. CyAdose was decreased to half and still after 6 months serumcreatinine was 122 mg/dl. No changes in hepatic transami-nases were seen in any patient.

Adverse events were more common in the CyA arm. A totalof 30 patients reported adverse events after taking CyA com-pared to 18 patients in the PPS arm (table 5). In the CyAarm, increased blood pressure and serum creatinine wereconsidered significant adverse events as was gross hematu-ria in the PPS arm.

Mild to moderate adverse events in the CyA arm includedinduced hair growth, gingival pain and hyperplasia, pares-thesias in extremities, abdominal pain, flushing, muscle painand shaking. In 1 patient the CyA dose was decreased to halfbecause of moderate adverse events. The total number ofpatients completing the study but not tolerating the initialCyA dose was 4 (14%). In the PPS arm the most commonadverse events were gastrointestinal disturbances, fatigue,headache and colic pelvic pain. At 6 months patients wereasked if they wanted to proceed with the current treatmentat their cost. A total of 19 patients continued on CyA treat-ment and 4 patients continued on PPS treatment.

DISCUSSION

The changes in all measured parameters of clinical re-sponse were significant with CyA, which is not usually the

case in trials evaluating oral drug therapy for IC. This studyshowed alleviation of subjective symptoms in 75% of patientstreated with CyA, showing superior efficacy compared toPPS. The number of responders increased during the treat-ment of 6 months with CyA while in the PPS group there wasno change. Although there were more adverse events amongthose receiving CyA therapy the discontinuation rate wassimilar in both groups. The high rate of responders is inaccord with the clinical success of CyA reported previous-ly.6, 8 We used in this study a 6-point scale as a GRA tool,which is weighted toward a positive response. A 7-point bal-anced scale is recommended.9 Some previous controlled stud-ies with PPS also used the 6-point scale which enabled us tocompare our results with those. We believe that the patientswith symptoms much improved or even those completelycured (GRA 5 to 6) would have also been responders with thecentered 7-point GRA scale. Our study did not reach thehypothesized percentages of patients getting the response tomicturition charts. However, our study had the requiredpower to show a difference in primary and secondary endpoints between CyA and PPS.

Although it is recommended to compare a new drug for ICagainst placebo,9 we preferred to compare CyA with PPSwhich has been tested several times against placebo andaccepted for treatment of IC. As an investigator initiatedstudy the open label technique was chosen to make determi-nation of the individual CyA dose easier. This was a multi-center study in which 67% of patients were recruited in unitshaving no experience of CyA treatment for IC. Thus, most ofthe urologists did not have prior expectations on the efficacyof either of the study drugs. While most of the patients hadmore than 1 failed treatment modality in their history, theywere motivated for the use of either of the acting drugs.There was no difference in compliance between the groups.

PPS was well tolerated and the study period was longenough to see the clinical effect. Although our results on theefficacy of PPS are difficult to compare with those of previousstudies as there were different criteria for patient enrollmentand different end points, however, they are in accord with theresults from randomized trials testing PPS.4, 5, 10 PPS hasbeen shown to be ineffective in successfully treating patientswith IC meeting NIDDK criteria. It is possible that PPSworks better in patients with a milder form of disease or inearlier stages of the disease.11

The mean patient age of 58.0 � 13.9 years is higher than insome other studies of patients with IC. Mean symptomatictime before entering our study was 8.4 � 6.8 years. The longhistory of IC of our patients is partly explained by the un-awareness of IC among Finnish physicians. Patients have towait long with symptoms before being referred to a urologist.The ineffectiveness of the usual treatments for IC is anotherreason. In the CyA group 19 of 29 patients completing thestudy wanted to continue with treatment, which indicatesthe clinical effect of CyA in patients with refractory IC.

The clinical effect of CyA improved during longer treat-ment and the proportion of responders increased at everyfollowup visit. This might reflect the inhibition of chronicinflammation, which comes slowly and is seen as relief of IC

TABLE 4. Blood pressure and serum creatinine duringCyA treatment

Mean � SD

Baseline After 6 MosTreatment

Systolic blood pressure 147 � 22 145 � 18Diastolic blood pressure 82 � 16 87 � 9Serum creatinine 68 � 9 73 � 13

TABLE 5. Participants with at least 1 adverse event(worst reported)

No. (%)

Cyclosporine A Pentosan PolysulfateSodium

Grade 0—none 2 (6.3) 14 (44)Grade 1—mild 23 (72) 14 (44)Grade 2—moderate 4 (13) 3 (9.4)Grade 3—significant 3 (9.4) 1 (3)

Overall 30 (94) 18 (56)

TABLE 3. Responders

No. (%)

Cyclosporine A Pentosan PolysulfateSodium p Value

1 Mo 13 (41) 7 (22) 0.1173 Mos 20 (63) 8 (25) 0.0036 Mos 24 (75) 6 (19) �0.001

CYCLOSPORINE A AND PENTOSAN POLYSULFATE SODIUM FOR INTERSTITIAL CYSTITIS 2237

related symptoms. As a calcineurin inhibitor, CyA inhibits Tcell activation by blocking the transcription of cytokine genesamong other functions.12 In addition, CyA stabilizes mastcells.13 T cells and mast cells are seen in abundance in ICbladder wall.14, 15

Because of the anti-inflammatory effects of CyA, patientsshould have an active inflammation in the bladder for whichthe drug could intervene. However, the problem is in know-ing who among the patients with IC has an active inflamma-tion in the bladder. A post-hoc analysis showed that patientsachieving the best therapeutic effect with CyA had a highermean age, which might reflect an inflammatory pathophysi-ology of the long-standing disease.

Although CyA side effects were common, the same numberof patients still completed the study in both arms, which maybe at least partly explained by good treatment efficacy moti-vating patients to continue it. Altogether 7 of 32 patients(22%) did not tolerate the initial CyA dose and it had to bereduced in 4 patients, while 3 patients discontinued treat-ment. Blood pressure responded well to dose reduction whilein 1 patient the increased serum creatinine did not. However,after discontinuation of the study treatment after 6 monthsthe serum creatinine normalized. Our results suggest that ifthe patient tolerates the drug for the first month, it can beexpected that she or he will tolerate it for a longer treatmentperiod.

We selected the CyA dose of 3 mg/kg based on our previousexperience in the treatment of IC.6 The dose was aimedto be high enough to evaluate whether CyA would beeffective in patients with IC. The dose could probably belower in most patients and the optimal CyA dose should betitrated individually. This is supported by our finding that in4 patients whose dose was reduced by 50% due to increasedblood pressure or serum creatinine, IC symptoms were keptaway.

The costs of CyA and PPS in Finnish pharmacy are sub-stantial. Social security covers costs of all medical drugsprescribed by a physician exceeding a yearly limit of 600euros. This is reached in 3 months with 50 mg CyA twicedaily and in 6 months with 100 mg PPS 3 times daily.However, the cost was not the only reason all patients ben-efitting from treatment did not want to continue therapy.Being completely symptom-free, many of those in the CyAgroup wanted to see whether the response would last andthere would be no more need for medication.

Based on the results of the present trial, we would recom-mend CyA for patients with severe IC meeting NIDDK cri-teria, especially to those who do not benefit from other treat-ments. However, careful followup, including regular bloodpressure measurement and serum creatinine analysis, ismandatory. For a deeper understanding of the mechanism ofaction of CyA in IC, a study on bladder histology is war-ranted.

CONCLUSIONS

In this controlled randomized study we demonstrated theefficacy of CyA in IC. The effect of CyA on urinary symptomswas superior to PPS in all measured parameters. The num-ber of responders to CyA treatment increased throughout thestudy including 75% of patients at 6 months. Although ad-verse events were more common in patients treated withCyA, withdrawals were equally frequent in both study arms.We recommend CyA treatment for patients meeting theNIDDK criteria of IC. However, there is a need for carefulfollowup of patients during therapy.

APPENDIX: FINNIC STUDY GROUP

Helsinki University Hospital, FinlandJukka Sairanen, MDMirja Ruutu, MD, PhD

Tampere University Hospital, and Medical School, FinlandTeuvo L. J. Tammela, MD, PhD

Seinajoki Central Hospital, FinlandMikael Leppilahti, MD, PhD

Kuusankoski District Hospital, FinlandMarkku Multanen, MD, PhDMarkku Onali, MD

Oulu University Hospital, FinlandIlkka Paananen, MD

Paijat-Hame Central Hospital, Lahti, FinlandKari Lehtoranta, MD, PhD

Kymenlaakso Central Hospital, Kotka, FinlandTapio Forsell, MD

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