Method for treating the urinary bladder and associated structures using hyaluronic acid

A method of treating interstitial cystitis comprising contacting the internal bladder and associated structures in a mammal having interstitial cystitis with a solution containing hyaluronic acid having a molecular weight of not less than approximately 2.times.10.sup.5 Daltons in a concentration effective to treat the interstitial cystitis.

TECHNICAL FIELD 
The present invention relates to a novel method for treating the internal 
bladder and associated structures in a mammal comprising the step of 
contacting the internal bladder and associated structures in the mammal 
with a solution containing hyaluronic acid having a molecular weight of 
not less than approximately 2.times.10.sup.5 Daltons. More particularly, 
the present invention relates to a novel method for treating the internal 
bladder and associated structures in a mammal having interstitial cystitis 
comprising the step of contacting the internal bladder and associated 
structures in the mammal having interstitial cystitis with a solution 
containing hyaluronic acid having a molecular weight of not less than 
approximately 2.times.10.sup.5 Daltons in a concentration effective to 
treat the interstitial cystitis. 
BACKGROUND OF THE INVENTION 
In mammals, the unique tight junctions of bladder surface epithelial cells 
are the fundamental mechanism by which the bladder maintains its 
impermeability. However, the glycosaminoglycan layer on the luminal 
surface of the bladder wall may be an important defense mechanism for 
protecting the transitional epithelium from urinary irritants (Chelsky, M. 
et al. 1994. Journal of Urology, 151:346.). This glycosaminoglycan layer 
consists of mucopolysaccharides attached to a core protein that, in turn, 
is bound to a central hyaluronic acid string. This highly viscous, highly 
hydrophilic glycosaminoglycan layer protects the transitional epithelium 
of the bladder from irritants in the urine including, but not limited to, 
pathogens, microcrystals, proteins, calcium and carcinogens (Nickel, J. C. 
et al. 1993. Journal of Urology, 149:716). This glycosaminoglycan layer 
also prevents small, uncharged molecules such as urea from diffusing to 
and across the transitional epithelium. Thus, the glycosaminoglycan layer 
lining the bladder acts as a barrier between the environment within the 
lumen of the bladder, and the transitional epithelium of the bladder and 
protects this transitional epithelium from inflammation, infection, 
trauma, stone formation and carcinogenesis. 
Interstitial cystitis is a poorly understood bladder condition for which 
there is no universal effective treatment program (Fleischmann, J. D. et 
al. 1991. Journal of Urology, 146:1235). Symptoms include urgency for 
urination, increased frequency of urination and suprapubic pain usually 
relieved by voiding. Other symptoms include arthritis, spastic colon and 
low grade fever. Individuals with interstitial cystitis can be 
significantly disabled, and individuals with advanced interstitial 
cystitis can require major surgery in order to function. Although the 
etiology of interstitial cystitis remains unexplained, it has been 
suggested that abnormalities of or deficiencies in the glycosaminoglycan 
layer lining the transitional epithelium of the bladder may be a primary 
defect. (Eldrup J. 1983. British Journal of Urology. 55:488). These 
abnormalities or deficiencies may enable increased permeability of the 
transitional epithelium (Parsons, E. L. et al. 1990. Journal of Urology, 
143:690) and this increased permeability may enable urinary solutes to 
gain access to the subepithelial tissue and to induce an irritative, 
inflammatory response that contributes to the symptoms of interstitial 
cystitis. Therefore, as interstitial cystitis may be related to an 
abnormality or deficiency in the glycosaminoglycan layer lining the 
transitional epithelium of the bladder, temporary replacement of this 
defective glycosaminoglycan layer with a defined glycosaminoglycan that 
protects the transitional epithelium may be effective in the treatment of 
interstitial cystitis. 
There is no standard treatment for interstitial cystitis. Among the 
treatments used are hydraulic distention of the bladder, oral 
amitriptyline or sodium pentosanpolysulfate, intravesical instillation of 
dimethylsulfoxide, oxychlorosene sodium, silver nitrate, heparin, or of a 
composition comprising an angiostatic steroid and pentosanpolysulfate. 
However, both the efficacy and the effectiveness of these treatments is 
variable. 
Hydraulic distention of the bladder is done under general or spinal 
anesthesia for one to two minutes at a pressure of 80 to 100 cm H.sub.2 O. 
In one study using hydraulic distention of the bladder to treat 
interstitial cystitis, less than 55% of the patients treated reported 
relief immediately after treatment and only 2% reported relief six months 
after treatment (Hanno P. M. et al. 1991. Semin Urology, 9:143). 
Instillation of dimethylsulfoxide (DMSO) into the bladder for six to eight 
weeks resulted in a 53% response rate to DMSO versus an 18% response rate 
to placebo, with the average length of response being six months 
(Perez-Marrero, R. et al. 1967. Journal of Urology, 98: 671). 
Pharmacological effects of DMSO include membrane penetration, enhanced 
drug absorption, anti-inflammatory and analgesic effects, collagen 
dissolution, muscle relaxation and mast cell histamine release. Side 
effects include increased vesicle irritability and garlic-like breath 
odor. 
Equivalent results to instillation of DMSO have been reported with 
oxychlorosene sodium (Messing, E. M. et al. 1978. Urology, 12:381). 
However instillation of oxychlorosene sodium requires anesthesia because 
of intense discomfort. 
Sodium pentosanpolysulfate is a low molecular weight synthetic 
glycosaminoglycan (U.S. Pat. No. 4,524,066 to Wolf) and is characterized 
by very low viscosity and high electronegativity. 
U.S. Pat. No. 4,820,693 to Gillespie (Gillespie '693) discloses a 
composition and method for arresting angiogenesis and cell, capillary or 
membrane leakage comprising either oral or intravesical administration of 
an angiostatic steroid and pentosanpolysulfate. The molecular weight of 
the pentosanpolysulfate for use in Gillespie '693 is between 
1.6.times.10.sup.3 and 6.times.10.sup.3 Daltons, and is preferably about 
2.times.10.sup.3 Daltons. U.S. Pat. No. 4,966,890 to Gillespie (Gillespie 
'890) discloses a composition and method for treating interstitial 
cystitis comprising either oral or intravesical administration of an 
angiostatic steroid and pentosan-polysulfate. Gillespie '890 teaches that 
pentosanpolysulfate can be used in place of heparin and that 
pentosanpolysulfate, in combination with an angiostatic steroid, cures 
interstitial cystitis by arresting angiogenesis, cell membrane leakage and 
capillary leakage or exchange in the bladder. 
U.S. Pat. No. 5,180,715 to Parsons (Parsons '715) also discloses the use of 
pentosanpolysulfate for treating interstitial cystitis. Parsons '715 
provides data to show that oral pentosanpolysulfate at doses in excess of 
100 mg per day are most effective for treating interstitial cystitis. 
Parsons '715 also suggests, but provides no data to show, that 
intravesical instillation of pentosanpolysulfate is useful for treating 
interstitial cystitis. Parsons '715 teaches that pentosanpolysulfate can 
be used in place of heparin and that pentosanpolysulfate acts to block 
bacterial adherence to the transitional epithelium of the bladder. 
Pentosanpolysulfate as disclosed in Gillespie '693, in Gillespie '890 and 
in Parsons '715 is a low viscosity glycosaminoglycan. As interstitial 
cystitis may be related to a defect in the high viscosity 
glycosaminoglycan layer on the luminal surface of the bladder, 
intravesical administration of the low viscosity pentosanpolysulfate would 
not provide adequate protection to the transitional epithelium of the 
bladder and associated structures. Therefore, what is needed is a highly 
viscous, highly hydrophilic substance which will coat the transitional 
epithelium of the bladder and associated structures. Such a highly 
viscous, highly hydrophilic substance can provide a barrier between 
irritants within the lumen of the bladder and associated structures and 
the transitional epithelium lining the bladder and associated structures. 
Hyaluronic acid (HA) is a heteropolysaccharide consisting of alternating 
residues of D-glucuronic acid and N-acetylglucosamine. HA is a linear 
polymer with a molecular weight of up to 13.times.10.sup.6 Daltons. It is 
found in connective tissue, in joint synovial fluid, in ocular vitreous 
humor, in umbilical cord, in cocks comb and is synthesized by some 
bacteria including, but not limited to streptococcal species. High 
molecular weight HA inhibits lymphocyte migration (Balzas E. A. et al. 
1973. In: Biology of Fibroblasts. Academic Press. pp. 237-252), and the 
phagocytic and chemotactic capacities of neutrophils and leukocytes are 
also inhibited. (Brandt, K. D. 1974. Clinical Chemical Acta 55:307). 
HA is highly viscous, highly electronegative and highly hydrophilic. It has 
been found that a high molecular weight fraction of HA provides 
unexpectedly excellent results in the treatment of interstitial cystitis. 
SUMMARY OF THE INVENTION 
Briefly, the present invention comprises a method for treating interstitial 
cystitis in a mammal with interstitial cystitis comprising the step of 
contacting the internal surface of the bladder and associated structures 
which include the ureters and urethra in a mammal having interstitial 
cystitis with a solution containing HA having a molecular weight of not 
less than approximately 2.times.10.sup.5 Daltons in a concentration 
effective to treat the interstitial cystitis. 
This invention also includes a method for treating bladder trauma, bladder 
irritation and bladder infection in a mammal with bladder trauma, bladder 
irritation or bladder infection comprising the step of contacting the 
internal surface of the bladder and associated structures in a mammal 
having bladder trauma, bladder irritation or bladder infection with a 
solution containing HA having a molecular weight of not less than 
approximately 2.times.10.sup.5 Daltons in a concentration effective to 
treat the bladder trauma, bladder irritation or bladder infection. 
This invention further comprehends the addition of various substances 
including, but not limited to, antibiotics, bacterial cell extracts, 
viruses, cytokines and interferons to the HA composition for use in 
treating interstitial cystitis, bladder trauma, bladder irritation and 
bladder infection. 
It is an object of the present invention to provide a method for treating 
interstitial cystitis in a mammal with interstitial cystitis by contacting 
the internal surface of the bladder and associated structures with a 
solution containing HA having a molecular weight of not less than 
approximately 2.times.10.sup.5 Daltons in a concentration effective to 
treat the interstitial cystitis. 
It is also an object of the present invention to provide a method for 
treating trauma, irritation and infection of the lining of the renal 
pelvis, ureters, bladder and urethra in a mammal with trauma, irritation 
and infection of the lining of the renal pelvis, ureters, bladder and 
urethra by contacting the internal surface of the renal pelvis, ureters, 
bladder and urethra with a solution containing HA having a molecular 
weight of not less than approximately 2.times.10.sup.5 Daltons in a 
concentration effective to treat the trauma, irritation and infection of 
the lining of the renal pelvis, ureters, bladder and urethra. 
Other objects, features and advantages of the present invention will become 
apparent upon reading the following detailed description of the preferred 
embodiment of the invention when taken in conjunction with the appended 
claims. 
DETAILED DESCRIPTION OF THE INVENTION 
As used herein, the phrase "internal surface of the bladder" refers to the 
surface of the bladder which is lined by transitional epithelium. 
As used herein, the phrase "associated structures" refers to the ureters 
and urethra. 
The present invention is directed to a method for treating interstitial 
cystitis in a mammal with interstitial cystitis by contacting the internal 
surface of the bladder and associated structures with a solution 
containing HA having a molecular weight of not less than approximately 
2.times.10.sup.5 Daltons in a concentration effective to treat the 
interstitial cystitis. It has been discovered that HA and salts thereof, 
having a molecular weight of not less than approximately 2.times.10.sup.5 
Daltons, unexpectedly, is successful in treating interstitial cystitis in 
a mammal with interstitial cystitis. 
The HA for use in this invention has a molecular weight of not less than 
approximately 2.times.10.sup.5 Daltons. More preferably the HA has a 
molecular weight between approximately 6.times.10.sup.5 and 
7.3.times.10.sup.5 Daltons. Most preferably the HA has a molecular weight 
of between approximately 6.0.times.10.sup.5 and 7.0.times.10.sup.5 
Daltons. 
Various methods for obtaining molecular weight fractions of HA are 
available. These include fractionation of HA prepared from cartilage, 
fractionation of HA produced from bacterial fermentation and purchase of 
molecular weight fractions of HA from commercial sources including, but 
not limited to Fluka Chemical Corporation, 908 South Second Street, 
Ronkonkoma, N.Y. 11779 and Genzyme Corporation, One Kendall Square, 
Cambridge, Mass. 02139. 
The HA for use in the present invention is present in a concentration from 
about 0.01 mg/ml to about 25 mg/ml. More preferably the HA is present in a 
concentration from about 0.1 mg/ml to about 2 mg/ml. Most preferably the 
HA is present in a concentration from approximately 0.4 mg/ml to about 1.2 
mg/ml. The HA is solubilized in a pharmaceutically acceptable buffer 
including, but not limited to, physiological saline and phosphate buffered 
saline. However, it is to be understood that any of the physiological 
buffers known to those skilled in the art to be pharmaceutically 
acceptable for contacting the surface of the bladder and associated 
structures in a mammal can be used in the present invention. 
The HA solution for use in the present invention may further include an 
antibiotic effective for treating interstitial cystitis. Determination of 
the antibiotic and of the amount of the antibiotic to be included in the 
HA solution are well within the determination of those skilled in the art. 
The HA solution for use in the present invention may further include an 
immunotherapeutic agent including, but not limited to bacterial cell 
extracts such as mycobacterial cell wall extract and bacilli 
calmette-guerin, viruses, cytokines and interferons. 
The HA solution for use in the present invention is instilled into the 
bladder and associated structures in a volume of between approximately 5 
ml and 100 ml. More preferably the HA composition is instilled into the 
bladder and associated structures in a volume of between approximately 20 
ml and 70 ml. Most preferably, the HA composition is instilled into the 
bladder and associated structures in a volume of between approximately 40 
and 60 ml. 
The amount of HA to be instilled into the bladder and associated structures 
in the present invention is between approximately 5 mg and 100 mg. More 
preferably the amount of HA to be instilled into the bladder and 
associated structures is between approximately 20 mg and 60 mg. Most 
preferably the amount of HA to be instilled into the bladder and 
associated structures is between approximately 35 mg and 45 mg. 
The HA solution of the present invention may be administered from a 
container such as, but not limited to, a bottle. The HA composition may 
instilled into the bladder and associated structures using a urinary 
catheter. However, it is to be understood that any method known to those 
skilled in the art for contacting the internal surface of the bladder and 
associated structures in a mammal with a pharmaceutical solution can be 
used in the present invention. 
The HA solution should remain in contact with the bladder and associated 
structures for from approximately 30 minutes to 8 hours. More preferably 
from 30 minutes to 4 hours. Most preferably from 30 minutes to 2 hours. 
Treating interstitial cystitis in a mammal having interstitial cystitis 
with a solution containing HA by contacting the internal bladder and 
associated structures with HA and salts thereof, having an average 
molecular weight of not less than approximately 2.times.10.sup.5 Daltons, 
provides surprisingly good results in providing relief from the symptoms 
of interstitial cystitis without disturbing side effects.

EXAMPLE 1 
ISOLATION, PURIFICATION AND FRACTIONATION OF HYALURONIC ACID 
The following describes a method for the isolation, purification and 
fractionation of hyaluronic acid from cartilage for use in this invention. 
Pre-Treatment of Cocks Combs 
The preparation of sodium hyaluronate from frozen or fresh cocks combs 
involves the following steps: The cocks combs are minced, homogenized, 
dehydrated in acetone, and vacuum dried to a dry powder. The water content 
of the discarded acetone is less than 2.0%. The powder is digested 
enzymatically with papain in a buffered aqueous medium containing cysteine 
hydrochloride. The resulting mixture is clarified and ultrafiltered using 
a membrane with a molecular weight exclusion limit of 3.times.10.sup.4 
Daltons. The retained clear liquid has a pH between 5.0 and 7.0. The 
mucopolysaccharide content is 2.0 and 6.0 mg/ml sodium hyaluronate as 
determined by glucuronic acid assay. The amino acid content is greater 
than 6.0 mg/ml as determined by ninhydrin assay. 
Complexing, Fractionation, Precipitation 
NaCl (up to 0.1 M) and cetyl-pyridinium chloride (CPC) are added to the 
clear liquid with agitation. The precipitate is collected by 
centrifugation and washed three times in 0.01 M NaCl with 0.05% CPC. The 
precipitate is suspended in 0.05 M NaCl with 0.05% CPC with agitation and 
the cloudy supernatant is eliminated. This procedure is repeated several 
times using 0.1 M NaCl with 0.05% CPC. The precipitate is then dispersed 
in 0.3 M NaCl with 0.05% CPC with agitation and the extraction is repeated 
three times. The precipitate is then eliminated. The clear supernatants 
are pooled, brought to 0.23 M NaCl, CPC is added, the mixture is treated 
with Celite(R), and filtered. After Celite(R) treatment, the sodium 
hyaluronate content is 2.5-5.0 mg/ml as determined by glucuronic acid 
assay. 
Isolation of Hyaluronic Acid 
The filtrate is ultrafiltered using a membrane with a molecular weight 
exclusion limit of 3.times.10.sup.4 Daltons and the retained liquid is 
concentrated. This liquid is precipitated with 95% ethanol and 
centrifuged. The precipitate is dissolved in 0.1 M NaCl and precipitated 
again with 95% ethanol. The precipitate is collected and washed yielding a 
crude product having an average molecular weight of not less than 
approximately 2.5.times.10.sup.5 Daltons. The yield is equivalent to 0.6% 
of original fresh tissue. 
Purification of Hyaluronic Acid Fraction 
The precipitate is dissolved in pyrogen-free distilled water (10 mg/ml) and 
ultrafiltered using a membrane with a molecular weight exclusion limit of 
2.times.10.sup.5 Daltons without addition of supplementary water. This 
increases the concentration of molecules having a molecular weight greater 
than 2.times.10.sup.5 Daltons. Ultrafiltration is used to reduce the 
volume to 10% of original volume. Water is added to the concentrated 
solution and the operation is repeated twice. The concentrated solution is 
collected and is diluted with water to a concentration of 5 mg/ml 
hyaluronic acid. NaCl is added to bring the solution to 0.1 M and the 
solution is precipitated with four volumes of 95% ethanol. The precipitate 
is washed and then vacuum dried. 
This purified hyaluronic acid is polydisperse and has an average molecular 
weight, of not less than approximately 2.times.10.sup.5 Daltons. Methods 
for further fractionating this HA into different molecular weight 
fractions are well known to those of ordinary skill in this art. Further 
methods for preparing purified HA of the molecular weights claimed in this 
invention are disclosed in U.S. Pat. No. 4,141,973 to Balzas which is 
incorporated by reference. 
EXAMPLE 2 
INTERSTITIAL CYSTITIS PILOT STUDY 
In this pilot study five patients with interstitial cystitis, receive 
intravesical instillation of 40 mg of hyaluronic acid having a molecular 
weight of 6.5.times.10.sup.5 Daltons in 40 ml to 70 ml sterile saline 
(USP). 
Outcome criteria for this pilot study are related to improvement of 
symptoms based on decreases in pre-therapy symptoms, pre-therapy pain, and 
pre-therapy urgency. 
SUBJECT 1 
PATIENT JM 
Interstitial cystitis patient JM (#002) fails treatment with both 
intravesical heparin instillation and oral pentosanpolysulfate. JM is 
treated according to the study protocol. Forty mg of HA having a molecular 
weight of approximately 6.5.times.10.sup.5 Daltons in 50 ml of normal 
saline (USP) is instilled into the bladder under sterile conditions using 
a urethral catheter. The catheter is removed and the HA solution is 
maintained in the bladder for 30 minutes. The treatment is repeated weekly 
for 7 weeks After the 7th treatment, the patient reports a marked 
improvement in suprapubic pain and in urgency of urination. The treatment 
is repeated 4 times during the following 17 weeks. After the last 
treatment, the patient reports a 100% improvement in suprapubic pain and 
improvement in urgency. No side effects of the HA treatment are reported 
by the patient. 
SUBJECT 2 
PATIENT GH 
Interstitial cystitis patients GH (#003) fails treatment with oral 
propantheline bromide (2-hydroxyethyl)-diisopropylmethylammonium bromide 
xanthene-9-carboxylate, phenylpropanolamine hydrochloridene and 
guaifenesin. GH is treated according to the study protocol. Forty mg of HA 
having a molecular weight of approximately 6.5.times.10.sup.5 Daltons in 
50 ml of normal saline (USP) is instilled into the bladder under sterile 
conditions using a urethral catheter. The catheter is removed and the HA 
solution is maintained in the bladder for 60 minutes. The treatment is 
repeated 4 times during an approximately 12 week period. After the last 
treatment, the patient reports a 100% improvement in pre-therapy symptoms, 
pre-therapy pain and pre-therapy urgency. No side effects of the HA 
treatment are reported by the patient. 
SUBJECT 3 
PATIENT LB 
Interstitial cystitis patient LB (#001) fails treatment with intravesical 
infusion of DMSO and heparin. LB is treated according to the study 
protocol. Forty mg of HA having a molecular weight of approximately 
6.5.times.10.sup.5 Daltons in 50 ml of normal saline (USP) is instilled 
into the bladder under sterile conditions using a urethral catheter. The 
catheter is removed and the HA solution is maintained in the bladder for 
45 minutes. The treatment is repeated weekly for 5 weeks with significant 
improvement in pre-therapy symptoms, pre-therapy pain and pre-therapy 
urgency. Due to an unrelated illness, treatment is interrupted for 
approximately 7 weeks and symptoms return. After two subsequent 
treatments, the patient is again improved. Again, due to an unrelated 
illness, treatment is interrupted for 13 weeks and symptoms return. After 
two subsequent treatments, the patient reports no improvement in symptoms 
and treatment is discontinued at the patients request. 
SUBJECT 4 
PATIENT MM 
Interstitial cystitis patients MM (#004) is treated according to the study 
protocol. Forty mg of HA having a molecular weight of approximately 
6.5.times.10.sup.5 Daltons in 50 ml of normal saline (USP) is instilled 
into the bladder under sterile conditions using a urethral catheter. The 
catheter is removed and the HA solution is maintained in the bladder for 
50 minutes. The treatment is repeated 9 times over a 22 week period. After 
the last treatment, the patient reports improvement in pre-therapy 
symptoms, in pre-therapy pain and in pre-therapy urgency. Although the 
patient reports no side effects from the HA treatment, the patient elects 
to discontinue HA treatment. 
SUBJECT 5 
PATIENT MS 
Interstitial cystitis patients MS (#006) is treated according to the study 
protocol. Forty mg of HA having a molecular weight of approximately 
6.5.times.10.sup.5 Daltons in 50 ml of normal saline (USP) is instilled 
into the bladder under sterile conditions using a urethral catheter. The 
catheter is removed and the HA solution is maintained in the bladder for 
60 minutes. The treatment is repeated weekly for 7 weeks. At the end of 
the 7th week there is a marked improvement in pre-therapy symptoms, in 
pre-therapy pain and in pre-therapy urgency. Four maintenance treatments 
are given during the following 16 months. Throughout and at the end of 
each of the maintenance treatments, the marked improvement is maintained. 
EXAMPLE 3 
INTERSTITIAL CYSTITIS STUDY 
This study is a randomized, double-blind, placebo-controlled multi-center 
trial of patients in a two-armed protocol. In this study, 75 patients will 
be randomized to receive intravesical instillations of hyaluronic acid 
having a molecular weight of approximately 6.5.times.10.sup.5 Daltons 
(experimental) or intravesical instillations of normal saline (control). 
Inclusion criteria for this study include: 
1. &gt;18 years of age 
2. diagnosed with interstitial cystitis 
3. untreated or failure of previous treatment 
4. two or more of following findings present 
a. suprapublic, uretheral, or perineal pain 
b. chronic inflammation or mast cell infiltration on cystoscopy or biopsy 
with no evidence of malignancy 
c. hydrodistension under anesthesia to 80 to 100 cm H.sub.2 O pressure with 
glomerulations (multiple petechiae), bloody effluent and diminished 
bladder capacity 
d. sterile bacterial urine cultures and no evidence of acid fast bacilli 
e. decreased compliance on cystometrogram 
f. pain on bladder filling (diminished by emptying) 
Exclusion criteria for this study include: 
1. benign or malignant bladder tumors 
2. evidence of vesicoureteral reflux or urethral diverticulum 
3. uterine, cervical, vaginal or urethral cancer, or prior pelvic or 
bladder radiation 
4. UTI, vaginitis, prostatitis 
5. bladder or lower ureteral calculi 
6. active herpes (herpes virus type II) 
7. positive urine cytology 
8. cystometrogram capacity &gt;400 cc, absence of sensory urgency or unstable 
bladder 
9. waking frequency &lt;5 in 12 hours 
10. neurogenic bladder dysfunction 
11. active for interstitial cystitis treatment within 1 month of enrollment 
in study 
Outcome criteria for this study include: 
1. Complete Response (CR): Improvement of symptoms with a &gt;75% decrease in 
pre-therapy symptom evaluation, pre-therapy visual analog (VAS) pain scale 
and pre-therapy visual analog (VAS) urgency scale. 
2. Partial Response (PR): Incomplete resolution of symptoms and a 50-74.99% 
decrease in pre-therapy symptom evaluation, pretherapy VAS pain scale and 
pre-therapy VAS urgency scale. 
3. Failure (F): Incomplete resolution of symptoms with a &lt;50% decrease in 
pre-therapy symptom evaluation, pre-therapy VAS pain scale and pre-therapy 
VAS urgency scale. 
Treatment protocols for this study include: 
Each patient randomized to receive the HA treatment of the present 
invention receives intravesical instillation of 40 mg of HA having a 
molecular weight of approximately 6.5.times.10.sup.5 Daltons in 50 ml of 
normal saline (USP). Under sterile conditions, a uretheral catheter is 
introduced into the bladder and any residual urine is removed and sent for 
bacterial culture. Fifty ml of the HA composition is instilled into the 
bladder and the catheter is removed. The patient is asked to retain the HA 
solution as long as possible, but for a minimum of 30 minutes. 
The HA instillation is given 1.times./week for 4 weeks followed by 
maintenance instillation 1.times./4 weeks for 20 weeks. Therapy is 
discontinued at 24 weeks after the first HA instillation. The effects of 
HA treatment are assessed at weeks 4, 8, 12, 16, 20, 24 and 28 of 
treatment using a symptom evaluation form, a VAS pain scale score and a 
VAS urgency scale score. 
The long term effects of HA treatment are assessed at weeks 32, 38 and 48 
using a symptom evaluation form, a VAS pain scale score, a VAS urgency 
scale score and a quality of life questionnaire. 
Each patient randomized to receive the placebo (normal saline) receives 
intravesicular instillation of 50 ml of saline 1.times./week for 4 weeks 
and 1.times./4 weeks for 8 weeks. 
Thus far, results are available for 14 patients entered into the study at 
variable time points within the study protocol. These results are 
summarized in TABLE I. 
__________________________________________________________________________ 
INTERSTITIAL CYSTITIS 
Date of 
Patient 
1st Tx 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
Week 
# (m/d/y) 
4 8 12 16 20 24 28 32 38 48 
__________________________________________________________________________ 
01 940615 
CR PR PR CR CR CR CR 
02 940728 
PR CR PR CR PR 
03 940802 F PR PR 
04 940916 
F PR F PR 
05 
06 941004 F PR 
07 941005 
F PR PR 
08 941007 
F PR 
09 941027 PR 
10 941026 
PR PR CR 
11 941106 
F F 
12 941107 
PR PR CR 
13 941108 
CR CR CR 
14 941118 
F CR 
15 941222 
F F 
__________________________________________________________________________ 
Response to Treatment: CR -- Complete Response, PR -- Partial Response, F 
-- Failure 
CR = 75-100% 
PR = 50-75% 
F = &lt;50% 
These findings show that high molecular weight hyaluronic acid instilled 
into the bladder and associated structures is an effective treatment for 
interstitial cystitis and ameliorates the symptoms of interstitial 
cystitis. 
Although the invention has been described to reference to particular means, 
materials and examples, it is to be understood that the invention is not 
limited to the particulars disclosed and extends to all equivalents within 
the scope of the claims.