PP

Review
Received: July 9, 2008 Accepted: July 28, 2008
Address correspondence to: Dr. Hann-Chorng Kuo, Department of Urology, Buddhist
Tzu Chi General Hospital, 707, Section 3, Chung Yang Road, Hualien, Taiwan
E-mail: [email protected]
Incont Pelvic Floor Dysfunct 2009; 3(2):33-35
Intravesical Treatment for Interstitial Cystitis
Mei-Yu Jang, M.D., Hann-Chorng Kuo, M.D.
1
Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology
1
, Buddhist
Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan
ners||a| cys||s (C) |s a synorome o mysery |n uro|oy. C |s
characer|zeo by b|aooer pa|n assoc|aeo w|h urency, requency,
nocur|a, oysur|a ano ser||e ur|ne [1|. The o|anos|s o h|s o|sease
rema|ns unc|ear ano shou|o be baseo on he exc|us|on o oher
o|seases. The poss|b|e e|o|o|es o C are (1) a pos-|nec|on auo|m-
mune process, (2) mas ce|| ac|va|on |nouceo by |n|amma|on, ox|ns
or sress, (3) urohe||a| oysunc|on ano |ncreaseo permeab|||y o he
urohe||um, or (4) neuroen|c |n|amma|on. The pr|nc|p|es or rea-
men o C are baseo on (1) conro|||n he oysunc|ona| ep|he||um by
con|nua| rep|en|shmen o he |ycosam|no|ycan (GAG) |ayer, (2) |n-
h|b||n neuro|o|ca| hyperac|v|y by aom|n|sra|on o am|r|py||ne or
|m|pram|ne, (3) suppress|on o a||er|es w|h an|h|sam|nes, ano (4)
pa|n conro| w|h non-sero|o an|-|n|ammaory orus (SAD), Cox-2
|nh|b|ors or ranqu|||zers.
nraves|ca| reamen or C usua||y sars w|h hyoroo|sen|on o
he b|aooer. Hyoroo|sen|on o he b|aooer may be recommenoeo as
he |rs reamen cho|ce or pa|ens w|h C because | prov|oes re|a-
|ve|y h|h e|cacy. However, he shor oura|on o he e|cacy requ|res
a secono-||ne reamen op|on or beer manaemen o pa|ens w|h
C [2|. nraves|ca| meo|ca|ons such as hepar|n ano hepar|no|os (e..
soo|um penosan po|ysu|ae, hya|uron|c ac|o, chonoro||n su|phae),
o|mehy| su|phox|oe (DMSO) ano van|||o|os (capsa|c|n or res|n|eraox|n)
have been r|eo ano have shown o be eec|ve |n a por|on o C
pa|ens.
The aovanaes o |nraves|ca| reamen o C |nc|uoe: (1) oe||v-
ery o h|h oru concenra|ons |no he b|aooer, (2) |ow |nc|oence o
sysem|c s|oe eecs, (3) reouceo ora| oru |nerac|ons, ano (4) o|-
rec repa|r o b|aooer urohe||a| oe|c|s.
BLADDER HYDRODISTENTION
For he |nraves|ca| reamen o C, hyoroo|sen|on o he b|aooer
|s he |rs cho|ce or o|anos|s, b|opsy ano reamen. A|houh
hyoroo|sen|on |s eec|ve or re||e o b|aooer sympoms o C, he
sympoms usua||y recur soon ano repea hyoroo|sen|on |s necessary
[2|. Ur|ne rom pa|ens w|h C has been shown o |nh|b| urohe||a|
pro||era|on hrouh a pua|ve an|pro||era|ve acor ano o cona|n
oecreaseo |eve|s o hepar|n-b|no|n ep|oerma| rowh acor-||ke rowh
acor (HB-EGF) compareo w|h he conro| subjecs. B|aooer srech
|ncreaseo HB-EGF ano converse|y reouceo an|pro||era|ve acor
ac|v|y |n ur|ne rom pa|ens w|h C bu no |n he conro| subjecs up
o 2 weeks aer o|sen|on [3|. Pro|oneo hyoroo|sen|on unoer ep|-
oura| aneshes|a w|h |nraves|ca| pressure equa| o he mean arer|a|
pressure o he pa|en has been shown o |ve |on-erm bene|s.
G|ema|n e a| reaeo 65 consecu|ve C pa|ens ano ouno h|s rea-
men was eec|ve |n 60% o pa|ens a 6 monhs ano 43.3% a 1 year
[4|. Yamaoa e a| a|so hao s|m||ar herapeu|c resu|s. n he|r suoy,
aojuvan hyoroo|sen|on unoer ep|oura| aneshes|a was eec|ve or
70% o pa|ens or more han 3 monhs [5|. Pose e a| ouno ha o|s-
en|on w|h e|ecromo|ve oru aom|n|sra|on (EMDA) |n he oocor's
o|ce se|n was as eec|ve as hyoroo|sen|on o he b|aooer |n he
opera|n room [6|.
INTRAVESICAL HEPARIN THERAPY
Hepar|n |s known o m|m|c he GAG |ayer srucure, ano hereore,
| |s ra|ona| o rea C w|h |nraves|ca| hepar|n w|h he a|m o rep|en-
|sh|n he oeec|ve GAG |ayer |n he b|aooer. Parsons e a| reaeo 48
C pa|ens w|h |nraves|ca| hepar|n 10000 U hree |mes per week or
3 monhs. They reporeo 56% o pa|ens hao |mprovemen |n a 3-oay
vo|o|n o|ary ano cysomerorams a 3 monhs. The auhors conc|uoeo
ha |nraves|ca| hepar|n conro||eo sympoms |n more han 50% o C
pa|ens [7|. Kuo reaeo 40 C pa|ens who hao pos||ve KC| es re-
su|s w|h |nraves|ca| hepar|n 25000 U rea|neo or 2 hours, w|ce per
week or 3 monhs. The sympom scores o 29 (72.5%) pa|ens |m-
proveo by >50%. Urooynam|c suoy resu|s revea|eo s|n||can |m-
provemen |n he |rs sensa|on o ||||n ano b|aooer capac|y aer
hepar|n reamen [8|. A|houh here |s no consensus on he oose,
herapeu|c requency, or he reamen oura|on |n |nraves|ca| hepa-
r|n herapy, | has been sueseo ha |nraves|ca| hepar|n herapy
shou|o sar a a h|h requency |n he acue sae, w|h a reouceo
requency |n he subacue sae. Treamen shou|o con|nue |nerm|-
en|y |n he ma|nenance sae, ano shou|o no sop, even |n non-
responoers.
A comb|na|on o hepar|n ano a|ka||n|zeo ||ooca|ne has recen|y
been useo o rea C pa|ens [9|. Parsons e a| useo 40000 U hepar|n
w|h 3 mL 8.4% soo|um b|carbonae ano 1% (Group 1) or 2% ||ooca|ne
(Group 2) or |nraves|ca| reamen hree |mes per week or 2 weeks.
S|n||can |mmeo|ae sympom re||e aer a s|n|e reamen was noeo
|n 75% ano 94% o roups 1 ano 2 pa|ens, respec|ve|y, 50% o roup
2 pa|ens hao sympom re||e or 4 hours ano 80% o roup 2 pa|ens
reporeo s|n||can susa|neo sympom re||e aer 2 weeks.
INTRAVESICAL HYALURONIC ACID
Hya|uron|c ac|o |s a non-su|aeo mucopo|ysacchar|oe com-
ponen o he GAG |ayer ano |s be||eveo o be presen |n subep|he||a|
connec|ve |ssue o proec he b|aooer wa|| rom |rr|ans |n he ur|ne.
nraves|ca| reamen w|h h|s aen has been |nves|aeo |n C
pa|ens. Mora|es e a| reaeo 25 C pa|ens reracory o any rea-
men w|h 40 m hya|uron|c ac|o week|y or 4 weeks ano hen monh|y.
PQ
Review
They ouno an |n||a| 56% pos||ve response rae a week 4, ano a 71%
pos||ve response rae a week 12. The response was ma|na|neo un||
week 20, bu oecreaseo aer week 24 [10|. A recen prospec|ve, non-
ranoom|zeo suoy w|h a 3-year o||ow up |n 20 C pa|ens revea|eo
subjec|ve con|nu|n |mprovemen |n pa|n ano requency, w|h 55% o
pa|ens reaeo w|h |nraves|ca| hya|uron|c ac|o choos|n o con|nue
reamen or sympoma|c re||e [11|.
INTRAVESICAL CHONDROITIN SULPHATE
Chonoro||n su|phae |s a major componen o he GAG |ayer ano
compr|ses 1/3 o he oa| proeo|ycans on he b|aooer surace. A
oe|c| o chonoro||n su|phae proeo|ycans on he b|aooer urohe||um
has been oeeceo |n C pa|ens [12|. E|heen C pa|ens who hao
pos||ve KC| es resu|s hao |nraves|ca| |ns|||a|on o 40 mL o 0.2%
chonoro||n su|phae once per week or 4 weeks o||oweo by one rea-
men per monh or 12 monhs. Th|reen o he 18 pa|ens reaeo
(66.7%) hao |mprovemen |n he|r |ower ur|nary rac sympoms [13|.
INTRAVESICAL PPS TREATMENT
Because he ora| penosan po|ysu|phae (PPS) was eec|ve |n
rea|n C pa|ens, |nraves|ca| |ns|||a|on was |nves|aeo o see |
beer resu|s cou|o be oba|neo. Baoe e a| reaeo 10 C pa|ens w|h
300 m PPS |n 50 mL 0.9% sa||ne w|ce per week or 3 monhs ano 10
pa|ens w|h a p|acebo. Four o he reaeo pa|ens ano wo conro|
pa|ens hao s|n||can sympoma|c re||e. E|h con|nueo PPS herapy
ano our w|hou reamen hao sympoma|c re||e [14|.
INTRAVESICAL DMSO TREATMENT
DMSO prov|oes an an|-|n|ammaory eec, ana|es|a, musc|e
re|axa|on, ano a|era|on o he co||aen response ano has an |n|u-
ence on conouc|on ano neuroransm|ss|on |n he sensory nerves. A
concenra|ons o 10%, DMSO |nh|b|s mas ce|| secre|on, bu an |n||a|
|ncrease |n mas ce|| secre|on ano worseneo |ower ur|nary rac symp-
oms have been noeo a a concenra|on o 50% [15|. Pe||e o symp-
oms was reporeo |n 50% o C pa|ens reaeo w|h 50 mL o 50%
DMSO rea|neo or 15-20 m|nues, |ven once per week or 2-3 monhs.
However, he re|apse rae was 35%-40% our|n a 24 monh o||ow-up
per|oo [16|. The h|h concenra|on o DMSO has been houh o harm
he b|aooer wa||, resu||n |n a conraceo b|aooer aer repeaeo
|ns|||a|ons. Me|ch|or e a| ouno a 40% concenra|on o DMSO com-
p|ee|y ano |rrevers|b|y abo||sheo conrac|ons o ra b|aooers [17|.
INTRAVESICAL BCG TREATMENT
nraves|ca| bac|||us Ca|mee-Guer|n (BCG) |s an |mmuno|o|ca|
herapy or super|c|a| b|aooer cancer ano |s known o s|mu|ae he
Th1 cyok|ne pro||e. The use o BCG |n he reamen o C a|ms o
moou|ae |mmuno|o|c ano a||er|c responses |n he C b|aooer wa||
[18|. n a ooub|e-b||no, p|acebo-conro||eo suoy, 30 C pa|ens mee-
|n DDK cr|er|a rece|veo s|x week|y reamens w|h T|ce sra|n BCG
|ns|||a|on or a p|acebo ano were o||oweo-up or 8 monhs. There was
a 60% response rae |n he reaeo pa|ens ano a 27% rae |n he
conro| roup [19|. n |on-erm o||ow up, 89% o pa|ens who re-
sponoeo avorab|y aer he 6-week BCG reamen con|nueo o have
exce||en responses a 24-33 monhs [20|. However, he CCTG re-
cen|y reporeo he resu|s o a mu||-cener, ranoom|zeo, ooub|e-b||no,
p|acebo-conro||eo r|a| o |nraves|ca| BCG or he reamen o rerac-
ory C. Amon 265 pa|ens who rece|veo BCG or a p|acebo ano were
o||oweo-up or 34 weeks, he response rae was 12% or he p|acebo
ano 21% or BCG (p=0.062). On|y mar|na| sa|s|ca| s|n||cance was
observeo |n he seconoary oucomes (vo|o|n o|ary, pa|n, urency ano
C sympom |noex). A|houh he saey pro||e was accepab|e, |nrave-
s|ca| BCG reamen was cons|oereo |neec|ve |n reamen o rerac-
ory C [21|.
INTRAVESICAL VANILLOIDS
Van|||o|o recepors (VP1) have been ouno on he urohe||a| ce||s,
suburohe||a| sensory aerens ano smooh musc|e ce||s. VP1 co-|o-
ca||zes w|h P2X3 recepors, meo|a|n srech, pa|n ano nox|ous s|mu||.
Desens||za|on o VP1 recepors may oep|ee erm|na| nerve eno|ns
ano eno pa|n [22,23|. The mos popu|ar van|||o|o aens useo or c||n|-
ca| r|a|s |n C are capsa|c|n ano res|n|eraox|n. Th|ry-s|x pa|ens w|h
hypersens||ve b|aooers were ranoom|zeo o rece|ve |nraves|ca|
10 M capsa|c|n or p|acebo w|ce week|y or 1 monh. S|n||can |m-
provemen |n requency ano nocur|a was noeo |n he pa|ens reaeo
w|h capsa|c|n a he 6-monh o||ow-up exam|na|on. Boh roups ex-
per|enceo a s|n||can reouc|on |n pa|n a he eno o reamen ano a
he 6 monh o||ow-up eva|ua|on. However, no |mprovemen |n urency
was exper|enceo aer capsa|c|n |ns|||a|on [24|. nraves|ca| capsa|-
c|n herapy was a|so |nves|aeo |n Ta|wan. The auhor reaeo 10
pa|ens w|h C ano 10 w|h hypersens||ve b|aooers. Capsa|c|n |n a
10 M concenra|on was |ns|||eo |nraves|ca||y once per week or 6
weeks. There was a shor response per|oo |n e|h pa|ens w|h hyper-
sens||ve b|aooers (3-5 oays) ano |n wo C pa|ens (2-3 oays).
everhe|ess, no s|oe eecs were reporeo excep or severe |rr|a|n
sympoms aer reamen [25|.
Lazzer| e a| reaeo 18 C pa|ens w|h s|n|e ooses o 10 nM
res|n|eraox|n (PTX) or p|acebo. S|n||can |mprovemens |n requency,
nocur|a ano pa|n scores were noeo a 30 oays, bu herapeu|c e-
ecs were reouceo a 3 monhs [26|. The same auhor urher reaeo
|ve women w|h C w|h pro|oneo |nraves|ca| |nus|on o 10 nM PTX
or 10 oays. The pa|n score (6.7 o 3.2) oecreaseo aer reamen ano
rema|neo s|n||can|y |ower a 3 monhs. Frequency (11.3 o 8.7) ano
nocur|a (3.6 o 1.9) were a|so reouceo a 3 monhs [27|. n a pre||m|-
nary suoy, Pen ano Kuo ouno ha mu||p|e |nraves|ca| reamens
w|h PTX 10 nM once week|y or 4 weeks was we|| o|eraeo ano re-
ouceo b|aooer pa|n ano |ncreaseo he sympom score |n 58% o 12
women w|h chron|c C [28|. A|houh hese pre||m|nary suo|es seem
prom|s|n, a recen|y reporeo mu||-cener, ranoom|zeo, p|acebo-con-
ro||eo r|a| o assess he e|cacy ano saey o s|n|e-oose PTX o rea
C revea|eo no s|n||can o|erence beween PTX ano he p|acebo. n
163 C pa|ens reaeo w|h 10 nM, 50 nM, or 100 nM PTX or a p|acebo
|n a s|n|e |nraves|ca| reamen ano o||oweo up over 12 weeks, PTX
o|o no |mprove he overa|| sympoms, pa|n, urency, requency,
nocur|a, or averae vo|o vo|ume a 12 weeks. The b|aooer pa|n |n-
ouceo by PTX |ns|||a|on |ncreaseo a he h|her ooses [29|.
A|houh capsa|c|n or PTX seems heore|ca||y o be eec|ve on
C, he c||n|ca| resu|s oo no suppor he|r use, poss|b|y oue o unoer-
|y|n pahophys|o|o|es oher han van|||o|o recepor ac|va|on |n C
pa|ens. C b|aooer |s ||ke|y o have mu||p|e oeecs ano |n|ammaory
PR
Review
processes, reamen o C m|h no be eec|ve when a|m|n a a
s|n|e paho|oy.
CONCLUSIONS
nraves|ca| reamen w|h hepar|n, hya|uron|c ac|o, chonoro||n
su|phae, BCG, or DMSO or C |s eec|ve or some pa|ens. However,
he p|acebo eec shou|o be we|heo ano ranoom|zeo, ooub|e-b||no
r|a|s shou|o be unoeraken o oemonsrae he acua| herapeu|c e-
ecs o hese herapeu|c mooa|||es. By ar, |nraves|ca| hepar|n re-
ma|ns he reamen o cho|ce or ear|y C accoro|n o he suoy resu|s.
Comb|neo herap|es w|h hyoroo||aa|on, an|h|sam|nes, SAD, ano
an|cho||ner|cs m|h be bene|c|a| |n aoo||on o |nraves|ca| reamen.
Lon-erm herapy |s neeoeo o ensure a beer cure rae or C.
REFERENCES
1. Tait L: Cure of chronic perforating ulcer by the formation of an arti-
ficial vesico-vaginal fistula. Lancet 1870; 2:738.
2. Inoue R, Takahashi S, Sunaoshi K, Ichihara K, Masumori N,
Tsukamoto T: Hydrodistention of the bladder in patients with inter-
stitial cystitis--clinical efficacy and its association with immuno- his-
tochemical findings for bladder tissues. Hinyokika Kiyo 2006; 52:
765-768.
3. Tsai TC, Zhang CO, Shoenfelt JL, Johnson HW Jr, Warren JW,
Keay S: Bladder stretch alters urinary heparin-binding epidermal
growth factor and antiproliferative factor in patients with interstitial
cystitis. J Urol 2000; 163:1440-1444.
4. Glemain P, Riviere C, Lenormand L, Karam G, Bouchot O, Buzelin
JM: Prolonged hydrodistention of the bladder for symptomatic treat-
ment of interstitial cystitis: Efficacy at 6 months and 1 year. Eur Urol
2002; 41:79-84.
5. Yamada T, Murayama T, Andoh M: Adjuvant hydrodis-tension un-
der epidural anesthesia for interstitial cystitis. Int J Urol 2003; 10:
463-468.
6. Rose AE, Azevedo KJ, Payne CK: Office bladder distention with
electromotive drug administration (EMDA) is equivalent to disten-
tion under general anesthesia (GA). BMC Urol 2005; 5:14.
7. Parsons CL, Housley T, Schmidt JD, Lebow D: Treatment of inter-
stitial cystitis with intravesical heparin. Br J Urol 1994; 73:504-507.
8. Kuo HC: Urodynamic results of intravesical heparin therapy for
women with frequency urgency syndrome and interstitial cystitis. J
Formosan Med Assoc 2001; 100:309-314.
9. Parsons CL: Successful downregulation of bladder sensory nerves
with combination of heparin and alkalinized lidocaine in patients
with interstitial cystitis. Urology 2005; 65:45-48.
10. Morales A, Emerson L, Nickel JC, Lundie M: Intravesical hyaluronic
acid in the treatment of refractory interstitial cystitis. J Urol 1996;
156:45-48.
11. Kallestrup EB, Jorgensen SS, Nordling J, Hald T: Treatment of in-
terstitial cystitis with Cystistat: A hyaluronic acid product. Scand J
Urol Nephrol 2005; 39:143-147.
12. Hurst RE, Roy JB, Min KW, et al: A deficit of chondroitin sulfate
proteoglycans on the bladder uroepithelium in interstitial cystitis.
Urology 1996; 48:817- 821.
13. Steinhoff G, Ittah B, Rowan S: The efficacy of chondroitin sulfate
0.2% in treating interstitial cystitis. Can J Urol 2002; 9:1454-1458.
14. Bade JJ, Laseur M, Nieuwenburg A, van der Weele LT, Mensink
HJ: A placebo- controlled study of intravesical pentosanpolysulphate
for the treatment of interstitial cystitis. Br J Urol 1997; 79:168-171.
15. Parkin J, Shea C, Sant GR: Intravesical dimethyl sulfoxide (DMSO)
for interstitial cystitis--a practical approach. Urology 1997; 49(Suppl
5A):105-107.
16. Sant GR: Intravesical 50% dimethyl sulfoxide (Rimso-50) in treat-
ment of interstitial cystitis. Urology 1987; 29:17-21.
17. Melchior D, Packer CS, Johnson TC, Kaefer M: Dimethyl sulfoxide:
Does it change the functional properties of the bladder wall? J Urol
2003; 170:253-258.
18. Peters KM, Diokno AC, Steinert BW: Preliminary study on urinary
cytokine levels in interstitial cystitis: Does intravesical bacille
Calmette-Guerin treat interstitial cystitis by altering the immune profile
in the bladder? Urology 1999; 54:450-453.
19. Peters K, Diokno A, Steinert B, et al: The efficacy of intravesical
Tice strain baccilus Calmette-Guerin in the treatment of interstitial
cystitis: A double-blind, prospective, placebo controlled trial. J Urol
1997; 157:2090-2094.
20. Peters KM, Diokno AC, Steinert BW, Gonzalez JA: The efficacy of
intravesical bacillus Calmette-Guerin in the treatment of interstitial
cystitis: Long-term follow up. J Urol 1998; 159:1483-1486.
21. Mayer R, Propert KJ, Peters KM, et al: A randomized controlled trial
of intravesical bacillus calmette-guerin for treatment refractory in-
terstitial cystitis. J Urol 2005; 173:1186-1191.
22. Brady CM, Apostolidis A, Harper M, et al: Parallel changes in blad-
der suburothelial vanilloid receptor TRPV1 and pan-neuronal marker
PGP9.5 immunoreactivity in patients with neurogenic detrusor
overactivity after intravesical resiniferatoxin treatment. BJU Int 2004;
93:770-776.
23. Smet PJ, Moore KH, Jonavicius J: Distribution and colocalization of
calcitonin gene-related peptide, tachykinins, and vasoactive intesti-
nal peptide in normal and idiopathic unstable human urinary bladder.
Lab Invest 1997; 77:37-49.
24. Lazzeri M, Beneforti P, Benaim G, Maggi A, Lecci A, Turini D: Intrave-
sical capsaicin for treatment of severe bladder pain: A randomized
placebo controlled study. J Urol 1996; 156:947-952.
25. Kuo HC: Treatment of hypersensitive bladder and interstitial cystitis
by intravesical instillation of capsaicin. Tzu Chi Med J 1994; 6:239-
244.
26. Lazzeri M, Beneforti P, Spinelli M, Zanollo A, Barbagli G, Turini D:
Intravesical resiniferatoxin for the treatment of hypersensitive
disorder: A randomized placebo controlled study. J Urol 2000; 164:
676-679.
27. Lazzeri M, Spinelli M, Beneforti P, Malaguti S, Giardiello G, Turini
D: Intravesical infusion of resiniferatoxin by a temporary in situ drug
delivery system to treat interstitial cystitis: A pilot study. Eur Urol
2004; 45:98-102.
28. Peng CH, Kuo HC: Multiple intravesical instillations of low-dose
resiniferatoxin in the treatment of refractory interstitial cystitis. Urol
Int 2007; 78:78-81.
29. Payne CK, Mosbaugh PG, Forrest JB, et al: Intravesical resinifera-
toxin for the treatment of interstitial cystitis: A randomized, double-
blind, placebo controlled trial. J Urol 2005; 173:1590-1594.