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Successful Therapy of Interstitial Cystitis with Pentosanpolysulfate
0022-5347 /87 /1383-0513$02.00/0 THE JOURNAL OF UROLOGY
Copyright© 1987 by The Williams & Wilkins Co.
SUCCESSFUL THERAPY OF INTERSTITIAL CYSTITIS WITH PENTOSANPOLYSULFATE C. LOWELL PARSONS
AND
S. GRANT MULHOLLAND
From the Divisions of Urology, Departments of Surgery, University of California, San Diego, California, and Jefferson Medical School, Philadelphia, Pennsylvania
ABSTRACT
Sodium pentosanpolysulfate (Ehniron) is a synthetic, sulfated polysaccharide available in an oral form that is excreted into the urine. This drug was used in a double-blind fashion to evaluate its efficacy in the management of symptoms of interstitial cystitis. A dose of 100 mg. 3 times daily was used for a minimum of 4 months and was continued for longer than 18 months in some individuals. A total of 62 patients was evaluated from 2 different medical centers. Subjective improvements were greater in all parameters when the drug was compared to placebo therapy, with significant improvement in pain, urgency, frequency and nocturia. Objective improvement in average voided volumes was greater with the drug than with placebo (p equals 0.009). No significant difference was found between drug and placebo groups in the average number of daily voiding episodes. (J. Ural., 138: 513-516, 1987) Interstitial cystitis is a disease state characterized by severe urinary urgency, frequency, nocturia and pain. 1 Unfortunately, no successful long-term management is available and the symptoms leave afflicted individuals significantly disabled. Our investigations into the intrinsic antibacterial defenses of the bladder have shown that it is lined in part by a mucous layer containing sulfated glycosaminoglycans. This layer was found not only to prevent bacterial adherence but also to prevent experimentally induced infection. 2 As a result, it was believed that the mucus represented an important antibacterial defense mechanism. Subsequently, the mucous lining was found to behave as a surface wetting agent that prevents bacteria, proteins and ions from adhering to the underlying transitional cells. 3- 7 The nonspecific nature of this antiadherence phenomenon led us to believe that the glycosaminoglycan coating is an effective method by which the bladder partly adapts to its environment. 6 We believe that interstitial cystitis may result when there are problems with the bladder surface, which allow urinary substances to leak into the bladder wall and cause inflammation. Since the naturally occurring glycosaminoglycan layer can be replaced by intravesical instillation of sodium pentosanpolysulfate (not available in the United States2' 6 ' 7 ) we hoped that it could augment the natural surface glycosaminoglycans and compensate for mucosal leaks, thereby ameliorating the disease. For these reasons we administered pentosanpolysulfate to in dividuals with interstitial cystitis. Preliminary evidence suggested successful control8 and this double-blind study was conducted. MATERIALS AND METHODS
Study design. Patients were eligible for the study if they had at least 1 year of symptoms, consisting of urgency, frequency, nocturia and/or pain. They also were required to have negative urine cultures, a cystoscopic examination that showed an ulcer or petechial hemorrhage (after bladder distension), biopsy proved inflammation and negative cytology studies. At the initial visit each person filled out a questionnaire grading the symptoms of urgency, frequency, nocturia and pain. At subsequent visits the patient graded improvements as 0, 25, 50, 75 or 100 per cent. Micturitional profiles were obtained in Accepted for publication August 29, 1986. Supported by the Veterans Administration Medical Center, San Diego, California.
513
some patients (added after the study began) but not in all. The profiles were done before the study and at each visit, and consisted of a 3-day recording of each voided volume from which the average voided volume and number of daily voids could be determined. The patients were randomized to drug or placebo groups by the pharmacy to begin therapy (treatment A). Therapy was begun with 100 mg. pentosanpolysulfate (or a look-alike placebo) 3 times daily or 200 mg. twice daily, depending on which institution they attended. At the end of 3 months, if the patient failed to respond to therapy, cross-over to treatment B was begun (from drug to placebo or vice versa). If the patient responded to treatment A he or she returned in 3 more months, and if there still was a positive response cross-over to treatment B was instituted. To complete the study the patient had to fail arms A and B, or to have 2 successive visits (6 months) with a positive response. Statistics. The average improvement (0 to 100 per cent) seen for each subjective parameter was determined and the drug was compared to placebo therapy with the Mann-Whitney rank sum test. P values were recorded. In addition, the number of patients with an improvement in subjective symptoms of at least 50 per cent (considered significant improvement) was recorded and drug responses were compared to- placebo via chisquare analysis. For objective responses, as recorded on the micturitional profile, significant improvement in patients on drug versus placebo therapy were analyzed by use of the paired t test to compare average daily voiding episodes and volumes before and after therapy. In regard to daily voiding, the number of patients with at least 3 less voids per day was determined and individuals on drug therapy were compared to those on placebo via chi-square analysis. RESULTS
Of 75 patients randomized into the study 4 withdrew before they received medication and 9 failed to return to complete the study. Not all patients completed evaluation sheets properly, such that there was no post-treatment report on urgency in 2 and on frequency in 7 (table 1). Among the 62 patients who completed the study only a single side effect (skin rash) was noted in 1. There were 10 per cent male and 90 per cent female patients. Ulcers were present in 28 per cent of the patients and pain in 75 per cent. There were no abnormal serum tests, including
514
PARSONS AND MULHOLLAND
prothrombin time, partial thromboplastin time, lactic dehydrogenase, serum glutamic oxaloacetic and pyruvic transaminases, hematocrit or white blood count. The results of treatment arms A and B (after cross-over) for subjective symptoms in all patients on drug or placebo are summarized in table 2. The drug did better than placebo in all categories. Micturitional profile results are reported in table 3. The average voided volumes were significantly improved on drug therapy (p = 0.009) but not on placebo. The average number of voids per day was unchanged after drug or placebo therapy. Table 4 summarizes the results of patients who responded while on any therapy (drug or placebo). Significant subjective improvement was seen for all symptoms (pain having the best improvement). The micturitional profiles showed significant improvement in average voided volumes but not in average daily voiding episodes. The actual number of measured daily voids appears to be an insensitive method to follow improvement. Tables 1 and 5 contain the data for patients from treatment arm A (before any cross-overs). Despite the limited number of patients, most symptoms showed significant improvement. Even the voided volume showed a tendency towards significant increase (p = 0.06).
TABLE
3. Average number of daily voids and bladder volumes determined by micturitional profiles Placebo
No. pts. Av. No. daily voids:* Before therapy After therapy Net difference No. improved(%) Av. voided vol. (ml.):§ Before therapy After therapy Av. change
29
Drug 34
20.1 ± 9 20.8 ± 13t 0.7 6 (21)
18.9 ± 9 18.3 ± 10:j: -0.6 13 (38)
80.4 ± 42 84.6 ± 53:j: 4.2
85.2 ± 46 102.5 ± 5711 17.3
P values were determined by Student's t test. Each group represents the patients who were evaluated after cross-over, such that some received drug and placebo therapy. * Net difference represents the difference in voids per day before and after therapy. Number improved is the number of subjects with at least 3 less voids per day. In regard to this factor the drug did better than the placebo (p = 0.1). t p = 0.6. :j:p = 0.5. § There was a significant increase in bladder capacity in the drug group (p = 0.009) but not in the placebo group. 11 p = 0.009.
TABLE
4. Symptoms and objective improvement before and after
therapy in patients in treatment arms A and B N onresponders TABLE 1.
Results of 4 symptoms evaluated for patients in treatment arm A
Pain: No. improved/total(%) Av.% improvement* Urgency: No. improved/total(%) Av. % improvement* Frequency: No. improved/total(%) Av. improvement Nocturia: av. improvement*
Placebo
Drug
P Value
3/20 (15) 12.2 ± 14.3
12/27 (44) 33.0 ± 35
0.02 0.02
5/28 (18) 11.6 ± 17
12/32 (38) 25.4 ± 26
0.08 0.05
10/24 (42) -1.8 -0.9 ± 0.8
20/31 (65) -5.4 -2.1 ± 2.2
0.06 0.06 0.05
Each patient was only on 1 therapy, drug or placebo. Cross-overs were made subsequent to this arm (treatment arm B). In most parameters the drug did significantly better than placebo despite the limited numbers of individuals in each group. Pain and urgency data are given as the number of patients reporting at least a 50 per cent improvement versus the total number in each group, and as the average improvements reported in these symptoms by the patients (0, 25, 50, 75 and 100 per cent). Frequency results are reported as the percentage of patients with any improvement and as the average change reported by the patient after therapy. P values were obtained by comparing placebo to drug. P values to compare the percentage of patients with improvement were obtained by chisquare analysis, while the remainder were determined with the Mann-Whitney rank sum test. * Mean ± standard deviation.
No. voids: Before therapy After therapy Av. vol. (ml.): Before therapy After therapy Symptoms: Pain:j: Urgency:j: Frequency§ Nocturia§
23.2 26.5*
14.0 11.1 *
76.3 66.1 *
88.9 132.lt
37 (10.1) 43 (5.41) 43(-0.9) 43 (-0.2)
2. Results of 4 symptoms evaluated for all patients Placebo
Pain: No. improved/total(%) Av. % improvement* Urgency: No. improved/total(%) Av. % improvement* Frequency: No. improved/total(%) Av. improvement Nocturia: av. improvement*
Drug
P Value
7/38(18) 15.8 ± 26
19/42 (45) 33.0 ± 35
0.02
9/48 (19) 14.0 ± 24
21/42 (40) 27.6 ± 31
0.03 0.01
16/41 (39) -0.4 -0.5 ± 0.5
33/52 (63) -5.1 -1.5 ± 2.9
0.005 0.002 0.04
O.Dl
In all parameters the drug did significantly better than placebo. Responses were considered good only if the patient experienced at least 50 per cent improvement. For pain and urgency each patient reported the average per cent improvement that they experienced, and the value presented represents the average improvements noted for these symptoms for all patients in the group. Frequency results are reported as the percentage of patients with any improvement and as the average change reported by the patient after therapy. P values were obtained by comparing placebo to drug. Each group represents the patients who started on a treatment arm or were crossed over to an arm, such that some patients were on both arms. * Mean ± standard deviation.
15 23 21 22
(60.0) (53.2) (-9.3) (-2.9)
Not all patients had micturitional profiles and not all reported data on all symptoms. Some patients were crossed over. Responders had at least a 50 per cent over-all subjective improvement regardless of therapy. All symptoms showed significant improvement when nonresponders and responders were compared (p <0.005). In regard to objective improvement, bladder capacities were significantly larger for responders but average number of daily voids changed little. * p >0.3 compared to before therapy. t p = 0.01 compared to before therapy. :j: No. improved(%). § No. (change after therapy).
5. Average daily voided volume and number of daily voids per day determined by micturitional profiles before cross-over in treatment arm A
TABLE
Placebo TABLE
Responders
No. pts. Av. No. daily voids:* Before therapy After therapy Net difference Av. voided vol. (ml.)::j: Before therapy After therapy Net difference
Drug
16
21
18.8 19.5t 0.7
18.0 18.0 0.0
76.7 74.3t -2.4
93.8 106.9§ 13.1
Results before and after therapy were compared with Student's t test. Each group represents the initial treatment and no patient was on drug plus placebo. * No difference was noted between placebo and drug groups. t p = 0.6. :j: There was no change in the placebo group but the drug group had a somewhat significant increase in bladder capacity (p = 0.6). However, the relatively small number of patients prevented the attainment of greater significance. § p = 0.06. 11 P = o.3.
DISCUSSION
Interstitial cystitis is a disease characterized by the symptoms of urinary urgency, frequency, dysuria, nocturia and/or pain in the abdomen or perineum. The disease tends to be
SUCCESSFUL THERAPY OF INTERSTITIAL CYSTITIS WITH PENTOSANPOLYSULFATE
1
progressive, and in its severe states it often leads to social and emotional crippling. The pain and frequency may interfere with the ability of an individual to work or socialize, and the nocturia may lead to chronic sleep deprivation. Fortunately, the syndrome is rare. While essentially unknown, the pathogenesis of interstitial cystitis has been suggested to involve an autoimmune phenomenon or perhaps a local histamine release. Microscopically, one sees a range of bladder tissue reactions from mild inflammation in less severe cases to severe interstitial fibrosis with more advanced disease. For more details the reader is referred to the report of Walsh. 9 Conservative measures to control interstitial cystitis have included transurethral resection of acute ulcers, hydrodilation of the bladder and instillations of compounds, such as silver nitrate and oxychlorosene. 10• 11 All of these measures generally do help afflicted people but usually they will lose their efficacy with time, leading to progressively shorter remissions of disease. More recently, dimethyl sulfoxide has been used successfully to manage the symptoms of interstitial cystitis but it also may have diminishing activity with time. 12 • 13 Many drugs have been used to treat interstitial cystitis, including steroids, anticholinergics, antispasmodics, tricyclic antidepressants, antihistamines and a-blocking agents. These compounds usually produce no response. 13 Should a severely afflicted individual fail to respond to conservative measures, then a major operation may be required, such as cystolysis, augmentation cystoplasty or cystectomy with urinary diversion. Our investigations into the antibacterial defenses of the bladder have suggested that a basic nonspecific mechanism exists that helps to protect the bladder from many potentially harmful constituents in urine. On the basis of these studies we developed our rationale for treatment of interstitial cystitis with sodium pentosanpolysulfate. The bladder secretes and binds to its surface a mucous layer composed in part of glycosaminoglycans. When present on the mucosa! surface, bacterial adherence to the cells and the incidence of infection are reduced significantly. 2- 7 When heparin (a glycosaminoglycan) is instilled into the lumen of a mucous deficient bladder, it binds to the surface and prevents microbial adherence as effectively as native glycosaminoglycans. Pentosanpolysulfate is equally as effective as heparin in this regard and has the advantage of being available in an oral form, 3 to 6 per cent of which is excreted into the urine. 2- 7 Furthermore, oral pentosanpolysulfate has no demonstrable anticoagulant activity. Basic biochemical properties of sulfated glycosaminoglycans offer a plausible explanation for their antiadherence activity in the bladder. These extremely hydrophilic compounds bind water molecules tightly to their sulfated moities. 14- 16 Barium, calcium and even hydrogen ions, except at extremely low pH, do not displace this water. In essence, what develops is a molecular layer of water between the transitional cells and their environment. This water layer should block all highly charged compounds and distribute a weaker negative charge across the surface, thereby reducing electrochemical interactions. This theory is supported by our finding that the natural and synthetic polysaccharides block adherence of ionic calcium and proteins to the bladder surface. 6 In addition, Gill and associates found that adherence of calcium oxalate crystals is blocked by endogenous and exogenous glycosaminoglycans. 17• 18 We believe that inflammatory conditions of the bladder wall may be induced by urinary substances that leak past the transitional cells. It may well be that surface glycosaminoglycans plus the superficial specialized cells represent important barriers that protect the bladder. We place interstitial cystitis in this category. Based on this rationale we attempted to determine whether oral pentosanpolysulfate would be active in inducing a remission in patients with interstitial cystitis. Early
515
results in an open study suggested success at controlling the disease. 8 While interstitial cystitis may result from a defective glycosaminoglycan layer, more likely other surface mechanisms are faulty, such as the umbrella cells and/or substances in urine. The success of pentosanpolysulfate may be owing to providing a more active surface glycosaminoglycans defense (in the face of normal glycosaminoglycans) compensating for other weaknesses. In any event, we do not know the reasons for the activity of pentosanpolysulfate. In all subjective parameters that were followed in our patients the drug performed significantly better than placebo therapy and induced a good remission in 40 to 63 per cent of the subjects versus 18 to 39 per cent for placebo. One can always argue about the accuracy of the diagnosis of interstitial cystitis but since there is no definitive serum study to make such a diagnosis one must deal with the fact that it primarily is a symptom complex. Our patients were required to have the complex for a minimum of 1 year plus traditionally accepted cystoscopic findings of petechial hemorrhages or ulcers. Most importantly, since the study was performed in a double-blind fashion we believe that the evidence for the success of pentosanpolysulfate in the management of interstitial cystitis is valid. We thought that insufficient patients with this rare syndrome would be available to compile sufficient data to have significant results. To compensate for this factor the cross-over was added. However, when the data were analyzed before any cross-overs (tables 4 and 5), even with fewer numbers of patients, most symptoms and voided volumes showed significant improvement when patients on drug therapy were compared to those on placebo. Table 1 contains the results of objective and subjective symptoms of patients who claimed marked improvement to those who did not. Responders were markedly better in all subjective parameters followed and also had better results in regard to voided volumes compared to nonresponders. However, average daily voiding episodes showed little change between the 2 groups. When this syndrome is studied it would appear that any subjective parameters and the voided volume would be accurate to predict improvement but not the number of daily voiding episodes. Pain was the most sensitive symptom to monitor and the first to show a good response, followed by urgency and nocturia. Patients who responded to drug therapy showed improvement at 5 to 10 weeks and continued to improve during several months. Remissions of disease tended to be long-term. Of 25 individuals treated for more than 18 months (in an open fashion once they completed the study) only 1 broke through therapy. When the drug was terminated the disease reappeared within 3 to 12 weeks in 80 per cent of these patients. Individuals who failed to respond primarily were those with severe disease and average voided volumes significantly less than those of responders (table 1). It would appear that sodium pentosanpolysulfate has significant activity in controlling the symptoms of interstitial cystitis. While the mechanisms by which pentosanpolysulfate act are unknown, it is theorized that the drug works owing to activity on the bladder surface or in the urine. The drug was supplied by Pharmacia, Piscataway, New Jersey, and is not available in the United States. REFERENCES
Runner, G. L.: A rare type of bladder ulcer. Further notes with a report of eighteen cases. J.A.M.A., 70: 203, 1918. 2. Parsons, C. L.: Prevention of urinary tract infection by the exogenous glycosaminoglycan sodium pentosanpolysulfate. J. Urol., 1.
127: 167, 1982.
3. Parsons, C. L., Greenspan, C. and Mulholland, S. G.: The primary antibacterial defense mechanism of the bladder. Invest. Urol., 13: 72, 1975.
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PARSONS AND MULHOLLAND
4. Parsons, C. L., Greenspan, C., Moore, S. W. and Mulholland, S. G.: Role of surface mucin in primary antibacterial defense of bladder. Urology, 9: 48, 1977. 5. Parsons, C. L., Mulholland, S. G. and Anwar, H.: Antibacterial activity of bladder surface mucin duplicated by exogenous glycosaminoglycan (heparin). Infect. Immun., 24: 552, 1979. 6. Parsons, C. L., Stauffer, C. and Schmidt, J. D.: Bladder surface glycosaminoglycans: an efficient mechanism of environmental adaptation. Science, 208: 605, 1980. 7. Parsons, C. L., Pollen, J. J., Anwar, H., Stauffer, C. and Schmidt, J. D.: Antibacterial activity of bladder surface mucin duplicated in the rabbit bladder by exogenous glycosaminoglycan (sodium pentosanpolysulfate). Infect. Immun., 27: 876, 1980. 8. Parsons, C. L., Schmidt, J. D. and Pollen, J. J.: Successful treatment of interstitial cystitis with sodium pentosanpolysulfate. J. Urol., 130: 51, 1983. 9. Walsh, A.: Interstitial cystitis. In: Campbell's Urology, 4th ed. Edited by J. H. Harrison, R. F. Gittes, A. D. Perlmutter, T. A. Stamey and P. C. Walsh. Philadelphia: W. B. Saunders Co., vol. 1, sect. IV, chapt. 19, p. 633, 1978. 10. Wishard, W. N., Jr., Nourse, M. H. and Mertz, J. H. 0.: Use of clorpactin WCS 90 for relief of symptoms due to interstitial cystitis. J. Urol., 77: 420, 1957. 11. Pool, T. L. and Rives, H. F.: Interstitial cystitis: treatment with
silver nitrate. J. Urol., 51: 520, 1944. 12. Stewart, B. H. and Shirley, S. W.: Further experience with intravesical dimethyl sulfoxide in the treatment of interstitial cystitis. J. Urol., 116: 36, 1976. 13. Fowler, J. E., Jr.: Prospective study of intravesical dimethyl sulfoxide in treatment of suspected early interstitial cystitis. Urology, 18: 21, 1981. 14. Gregor, H. P.: Anticoagulant activity of sulfonate polymers and copolymers. In: Polymer Science and Technology. New York: Plenum Press, vol. 5, p. 51, 1975. 15. Gryte, C. C. and Gregor, H. P.: Poly-(styrene sulfonic acid)-poly(vinylidene fluoride) interpolymer ion-exchange membranes. I. Preparation and characterization. J. Polymer Sci., part A-2, Polymer Physics Edition, 14: 1839, 1976. 16. Gregor, H.P.: Fixed charge ultrafiltration membranes. In: Charged Gels and Membranes, Part 1. Edited by E. Selegny. Holland: D. Reidel, p. 235, 1976. 17. Gill, W. B., Ruggiero, K. and Straus, F. H., II: Crystallization studies in a urothelial-lined living test tube (the catheterized female rat bladder). I. Calcium oxalate crystal adhesion to the chemically injured rat bladder. Invest. Urol., 17: 259, 1980. 18. Gill, W. B., Jones, K. W. and Ruggiero, K. J.: Protective effects of heparin and other sulfated glycosaminoglycans on crystal adhesion to injured urothelium. J. Urol., 127: 152, 1982.
Copyright© 1987 by The Williams & Wilkins Co.
SUCCESSFUL THERAPY OF INTERSTITIAL CYSTITIS WITH PENTOSANPOLYSULFATE C. LOWELL PARSONS
AND
S. GRANT MULHOLLAND
From the Divisions of Urology, Departments of Surgery, University of California, San Diego, California, and Jefferson Medical School, Philadelphia, Pennsylvania
ABSTRACT
Sodium pentosanpolysulfate (Ehniron) is a synthetic, sulfated polysaccharide available in an oral form that is excreted into the urine. This drug was used in a double-blind fashion to evaluate its efficacy in the management of symptoms of interstitial cystitis. A dose of 100 mg. 3 times daily was used for a minimum of 4 months and was continued for longer than 18 months in some individuals. A total of 62 patients was evaluated from 2 different medical centers. Subjective improvements were greater in all parameters when the drug was compared to placebo therapy, with significant improvement in pain, urgency, frequency and nocturia. Objective improvement in average voided volumes was greater with the drug than with placebo (p equals 0.009). No significant difference was found between drug and placebo groups in the average number of daily voiding episodes. (J. Ural., 138: 513-516, 1987) Interstitial cystitis is a disease state characterized by severe urinary urgency, frequency, nocturia and pain. 1 Unfortunately, no successful long-term management is available and the symptoms leave afflicted individuals significantly disabled. Our investigations into the intrinsic antibacterial defenses of the bladder have shown that it is lined in part by a mucous layer containing sulfated glycosaminoglycans. This layer was found not only to prevent bacterial adherence but also to prevent experimentally induced infection. 2 As a result, it was believed that the mucus represented an important antibacterial defense mechanism. Subsequently, the mucous lining was found to behave as a surface wetting agent that prevents bacteria, proteins and ions from adhering to the underlying transitional cells. 3- 7 The nonspecific nature of this antiadherence phenomenon led us to believe that the glycosaminoglycan coating is an effective method by which the bladder partly adapts to its environment. 6 We believe that interstitial cystitis may result when there are problems with the bladder surface, which allow urinary substances to leak into the bladder wall and cause inflammation. Since the naturally occurring glycosaminoglycan layer can be replaced by intravesical instillation of sodium pentosanpolysulfate (not available in the United States2' 6 ' 7 ) we hoped that it could augment the natural surface glycosaminoglycans and compensate for mucosal leaks, thereby ameliorating the disease. For these reasons we administered pentosanpolysulfate to in dividuals with interstitial cystitis. Preliminary evidence suggested successful control8 and this double-blind study was conducted. MATERIALS AND METHODS
Study design. Patients were eligible for the study if they had at least 1 year of symptoms, consisting of urgency, frequency, nocturia and/or pain. They also were required to have negative urine cultures, a cystoscopic examination that showed an ulcer or petechial hemorrhage (after bladder distension), biopsy proved inflammation and negative cytology studies. At the initial visit each person filled out a questionnaire grading the symptoms of urgency, frequency, nocturia and pain. At subsequent visits the patient graded improvements as 0, 25, 50, 75 or 100 per cent. Micturitional profiles were obtained in Accepted for publication August 29, 1986. Supported by the Veterans Administration Medical Center, San Diego, California.
513
some patients (added after the study began) but not in all. The profiles were done before the study and at each visit, and consisted of a 3-day recording of each voided volume from which the average voided volume and number of daily voids could be determined. The patients were randomized to drug or placebo groups by the pharmacy to begin therapy (treatment A). Therapy was begun with 100 mg. pentosanpolysulfate (or a look-alike placebo) 3 times daily or 200 mg. twice daily, depending on which institution they attended. At the end of 3 months, if the patient failed to respond to therapy, cross-over to treatment B was begun (from drug to placebo or vice versa). If the patient responded to treatment A he or she returned in 3 more months, and if there still was a positive response cross-over to treatment B was instituted. To complete the study the patient had to fail arms A and B, or to have 2 successive visits (6 months) with a positive response. Statistics. The average improvement (0 to 100 per cent) seen for each subjective parameter was determined and the drug was compared to placebo therapy with the Mann-Whitney rank sum test. P values were recorded. In addition, the number of patients with an improvement in subjective symptoms of at least 50 per cent (considered significant improvement) was recorded and drug responses were compared to- placebo via chisquare analysis. For objective responses, as recorded on the micturitional profile, significant improvement in patients on drug versus placebo therapy were analyzed by use of the paired t test to compare average daily voiding episodes and volumes before and after therapy. In regard to daily voiding, the number of patients with at least 3 less voids per day was determined and individuals on drug therapy were compared to those on placebo via chi-square analysis. RESULTS
Of 75 patients randomized into the study 4 withdrew before they received medication and 9 failed to return to complete the study. Not all patients completed evaluation sheets properly, such that there was no post-treatment report on urgency in 2 and on frequency in 7 (table 1). Among the 62 patients who completed the study only a single side effect (skin rash) was noted in 1. There were 10 per cent male and 90 per cent female patients. Ulcers were present in 28 per cent of the patients and pain in 75 per cent. There were no abnormal serum tests, including
514
PARSONS AND MULHOLLAND
prothrombin time, partial thromboplastin time, lactic dehydrogenase, serum glutamic oxaloacetic and pyruvic transaminases, hematocrit or white blood count. The results of treatment arms A and B (after cross-over) for subjective symptoms in all patients on drug or placebo are summarized in table 2. The drug did better than placebo in all categories. Micturitional profile results are reported in table 3. The average voided volumes were significantly improved on drug therapy (p = 0.009) but not on placebo. The average number of voids per day was unchanged after drug or placebo therapy. Table 4 summarizes the results of patients who responded while on any therapy (drug or placebo). Significant subjective improvement was seen for all symptoms (pain having the best improvement). The micturitional profiles showed significant improvement in average voided volumes but not in average daily voiding episodes. The actual number of measured daily voids appears to be an insensitive method to follow improvement. Tables 1 and 5 contain the data for patients from treatment arm A (before any cross-overs). Despite the limited number of patients, most symptoms showed significant improvement. Even the voided volume showed a tendency towards significant increase (p = 0.06).
TABLE
3. Average number of daily voids and bladder volumes determined by micturitional profiles Placebo
No. pts. Av. No. daily voids:* Before therapy After therapy Net difference No. improved(%) Av. voided vol. (ml.):§ Before therapy After therapy Av. change
29
Drug 34
20.1 ± 9 20.8 ± 13t 0.7 6 (21)
18.9 ± 9 18.3 ± 10:j: -0.6 13 (38)
80.4 ± 42 84.6 ± 53:j: 4.2
85.2 ± 46 102.5 ± 5711 17.3
P values were determined by Student's t test. Each group represents the patients who were evaluated after cross-over, such that some received drug and placebo therapy. * Net difference represents the difference in voids per day before and after therapy. Number improved is the number of subjects with at least 3 less voids per day. In regard to this factor the drug did better than the placebo (p = 0.1). t p = 0.6. :j:p = 0.5. § There was a significant increase in bladder capacity in the drug group (p = 0.009) but not in the placebo group. 11 p = 0.009.
TABLE
4. Symptoms and objective improvement before and after
therapy in patients in treatment arms A and B N onresponders TABLE 1.
Results of 4 symptoms evaluated for patients in treatment arm A
Pain: No. improved/total(%) Av.% improvement* Urgency: No. improved/total(%) Av. % improvement* Frequency: No. improved/total(%) Av. improvement Nocturia: av. improvement*
Placebo
Drug
P Value
3/20 (15) 12.2 ± 14.3
12/27 (44) 33.0 ± 35
0.02 0.02
5/28 (18) 11.6 ± 17
12/32 (38) 25.4 ± 26
0.08 0.05
10/24 (42) -1.8 -0.9 ± 0.8
20/31 (65) -5.4 -2.1 ± 2.2
0.06 0.06 0.05
Each patient was only on 1 therapy, drug or placebo. Cross-overs were made subsequent to this arm (treatment arm B). In most parameters the drug did significantly better than placebo despite the limited numbers of individuals in each group. Pain and urgency data are given as the number of patients reporting at least a 50 per cent improvement versus the total number in each group, and as the average improvements reported in these symptoms by the patients (0, 25, 50, 75 and 100 per cent). Frequency results are reported as the percentage of patients with any improvement and as the average change reported by the patient after therapy. P values were obtained by comparing placebo to drug. P values to compare the percentage of patients with improvement were obtained by chisquare analysis, while the remainder were determined with the Mann-Whitney rank sum test. * Mean ± standard deviation.
No. voids: Before therapy After therapy Av. vol. (ml.): Before therapy After therapy Symptoms: Pain:j: Urgency:j: Frequency§ Nocturia§
23.2 26.5*
14.0 11.1 *
76.3 66.1 *
88.9 132.lt
37 (10.1) 43 (5.41) 43(-0.9) 43 (-0.2)
2. Results of 4 symptoms evaluated for all patients Placebo
Pain: No. improved/total(%) Av. % improvement* Urgency: No. improved/total(%) Av. % improvement* Frequency: No. improved/total(%) Av. improvement Nocturia: av. improvement*
Drug
P Value
7/38(18) 15.8 ± 26
19/42 (45) 33.0 ± 35
0.02
9/48 (19) 14.0 ± 24
21/42 (40) 27.6 ± 31
0.03 0.01
16/41 (39) -0.4 -0.5 ± 0.5
33/52 (63) -5.1 -1.5 ± 2.9
0.005 0.002 0.04
O.Dl
In all parameters the drug did significantly better than placebo. Responses were considered good only if the patient experienced at least 50 per cent improvement. For pain and urgency each patient reported the average per cent improvement that they experienced, and the value presented represents the average improvements noted for these symptoms for all patients in the group. Frequency results are reported as the percentage of patients with any improvement and as the average change reported by the patient after therapy. P values were obtained by comparing placebo to drug. Each group represents the patients who started on a treatment arm or were crossed over to an arm, such that some patients were on both arms. * Mean ± standard deviation.
15 23 21 22
(60.0) (53.2) (-9.3) (-2.9)
Not all patients had micturitional profiles and not all reported data on all symptoms. Some patients were crossed over. Responders had at least a 50 per cent over-all subjective improvement regardless of therapy. All symptoms showed significant improvement when nonresponders and responders were compared (p <0.005). In regard to objective improvement, bladder capacities were significantly larger for responders but average number of daily voids changed little. * p >0.3 compared to before therapy. t p = 0.01 compared to before therapy. :j: No. improved(%). § No. (change after therapy).
5. Average daily voided volume and number of daily voids per day determined by micturitional profiles before cross-over in treatment arm A
TABLE
Placebo TABLE
Responders
No. pts. Av. No. daily voids:* Before therapy After therapy Net difference Av. voided vol. (ml.)::j: Before therapy After therapy Net difference
Drug
16
21
18.8 19.5t 0.7
18.0 18.0 0.0
76.7 74.3t -2.4
93.8 106.9§ 13.1
Results before and after therapy were compared with Student's t test. Each group represents the initial treatment and no patient was on drug plus placebo. * No difference was noted between placebo and drug groups. t p = 0.6. :j: There was no change in the placebo group but the drug group had a somewhat significant increase in bladder capacity (p = 0.6). However, the relatively small number of patients prevented the attainment of greater significance. § p = 0.06. 11 P = o.3.
DISCUSSION
Interstitial cystitis is a disease characterized by the symptoms of urinary urgency, frequency, dysuria, nocturia and/or pain in the abdomen or perineum. The disease tends to be
SUCCESSFUL THERAPY OF INTERSTITIAL CYSTITIS WITH PENTOSANPOLYSULFATE
1
progressive, and in its severe states it often leads to social and emotional crippling. The pain and frequency may interfere with the ability of an individual to work or socialize, and the nocturia may lead to chronic sleep deprivation. Fortunately, the syndrome is rare. While essentially unknown, the pathogenesis of interstitial cystitis has been suggested to involve an autoimmune phenomenon or perhaps a local histamine release. Microscopically, one sees a range of bladder tissue reactions from mild inflammation in less severe cases to severe interstitial fibrosis with more advanced disease. For more details the reader is referred to the report of Walsh. 9 Conservative measures to control interstitial cystitis have included transurethral resection of acute ulcers, hydrodilation of the bladder and instillations of compounds, such as silver nitrate and oxychlorosene. 10• 11 All of these measures generally do help afflicted people but usually they will lose their efficacy with time, leading to progressively shorter remissions of disease. More recently, dimethyl sulfoxide has been used successfully to manage the symptoms of interstitial cystitis but it also may have diminishing activity with time. 12 • 13 Many drugs have been used to treat interstitial cystitis, including steroids, anticholinergics, antispasmodics, tricyclic antidepressants, antihistamines and a-blocking agents. These compounds usually produce no response. 13 Should a severely afflicted individual fail to respond to conservative measures, then a major operation may be required, such as cystolysis, augmentation cystoplasty or cystectomy with urinary diversion. Our investigations into the antibacterial defenses of the bladder have suggested that a basic nonspecific mechanism exists that helps to protect the bladder from many potentially harmful constituents in urine. On the basis of these studies we developed our rationale for treatment of interstitial cystitis with sodium pentosanpolysulfate. The bladder secretes and binds to its surface a mucous layer composed in part of glycosaminoglycans. When present on the mucosa! surface, bacterial adherence to the cells and the incidence of infection are reduced significantly. 2- 7 When heparin (a glycosaminoglycan) is instilled into the lumen of a mucous deficient bladder, it binds to the surface and prevents microbial adherence as effectively as native glycosaminoglycans. Pentosanpolysulfate is equally as effective as heparin in this regard and has the advantage of being available in an oral form, 3 to 6 per cent of which is excreted into the urine. 2- 7 Furthermore, oral pentosanpolysulfate has no demonstrable anticoagulant activity. Basic biochemical properties of sulfated glycosaminoglycans offer a plausible explanation for their antiadherence activity in the bladder. These extremely hydrophilic compounds bind water molecules tightly to their sulfated moities. 14- 16 Barium, calcium and even hydrogen ions, except at extremely low pH, do not displace this water. In essence, what develops is a molecular layer of water between the transitional cells and their environment. This water layer should block all highly charged compounds and distribute a weaker negative charge across the surface, thereby reducing electrochemical interactions. This theory is supported by our finding that the natural and synthetic polysaccharides block adherence of ionic calcium and proteins to the bladder surface. 6 In addition, Gill and associates found that adherence of calcium oxalate crystals is blocked by endogenous and exogenous glycosaminoglycans. 17• 18 We believe that inflammatory conditions of the bladder wall may be induced by urinary substances that leak past the transitional cells. It may well be that surface glycosaminoglycans plus the superficial specialized cells represent important barriers that protect the bladder. We place interstitial cystitis in this category. Based on this rationale we attempted to determine whether oral pentosanpolysulfate would be active in inducing a remission in patients with interstitial cystitis. Early
515
results in an open study suggested success at controlling the disease. 8 While interstitial cystitis may result from a defective glycosaminoglycan layer, more likely other surface mechanisms are faulty, such as the umbrella cells and/or substances in urine. The success of pentosanpolysulfate may be owing to providing a more active surface glycosaminoglycans defense (in the face of normal glycosaminoglycans) compensating for other weaknesses. In any event, we do not know the reasons for the activity of pentosanpolysulfate. In all subjective parameters that were followed in our patients the drug performed significantly better than placebo therapy and induced a good remission in 40 to 63 per cent of the subjects versus 18 to 39 per cent for placebo. One can always argue about the accuracy of the diagnosis of interstitial cystitis but since there is no definitive serum study to make such a diagnosis one must deal with the fact that it primarily is a symptom complex. Our patients were required to have the complex for a minimum of 1 year plus traditionally accepted cystoscopic findings of petechial hemorrhages or ulcers. Most importantly, since the study was performed in a double-blind fashion we believe that the evidence for the success of pentosanpolysulfate in the management of interstitial cystitis is valid. We thought that insufficient patients with this rare syndrome would be available to compile sufficient data to have significant results. To compensate for this factor the cross-over was added. However, when the data were analyzed before any cross-overs (tables 4 and 5), even with fewer numbers of patients, most symptoms and voided volumes showed significant improvement when patients on drug therapy were compared to those on placebo. Table 1 contains the results of objective and subjective symptoms of patients who claimed marked improvement to those who did not. Responders were markedly better in all subjective parameters followed and also had better results in regard to voided volumes compared to nonresponders. However, average daily voiding episodes showed little change between the 2 groups. When this syndrome is studied it would appear that any subjective parameters and the voided volume would be accurate to predict improvement but not the number of daily voiding episodes. Pain was the most sensitive symptom to monitor and the first to show a good response, followed by urgency and nocturia. Patients who responded to drug therapy showed improvement at 5 to 10 weeks and continued to improve during several months. Remissions of disease tended to be long-term. Of 25 individuals treated for more than 18 months (in an open fashion once they completed the study) only 1 broke through therapy. When the drug was terminated the disease reappeared within 3 to 12 weeks in 80 per cent of these patients. Individuals who failed to respond primarily were those with severe disease and average voided volumes significantly less than those of responders (table 1). It would appear that sodium pentosanpolysulfate has significant activity in controlling the symptoms of interstitial cystitis. While the mechanisms by which pentosanpolysulfate act are unknown, it is theorized that the drug works owing to activity on the bladder surface or in the urine. The drug was supplied by Pharmacia, Piscataway, New Jersey, and is not available in the United States. REFERENCES
Runner, G. L.: A rare type of bladder ulcer. Further notes with a report of eighteen cases. J.A.M.A., 70: 203, 1918. 2. Parsons, C. L.: Prevention of urinary tract infection by the exogenous glycosaminoglycan sodium pentosanpolysulfate. J. Urol., 1.
127: 167, 1982.
3. Parsons, C. L., Greenspan, C. and Mulholland, S. G.: The primary antibacterial defense mechanism of the bladder. Invest. Urol., 13: 72, 1975.
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4. Parsons, C. L., Greenspan, C., Moore, S. W. and Mulholland, S. G.: Role of surface mucin in primary antibacterial defense of bladder. Urology, 9: 48, 1977. 5. Parsons, C. L., Mulholland, S. G. and Anwar, H.: Antibacterial activity of bladder surface mucin duplicated by exogenous glycosaminoglycan (heparin). Infect. Immun., 24: 552, 1979. 6. Parsons, C. L., Stauffer, C. and Schmidt, J. D.: Bladder surface glycosaminoglycans: an efficient mechanism of environmental adaptation. Science, 208: 605, 1980. 7. Parsons, C. L., Pollen, J. J., Anwar, H., Stauffer, C. and Schmidt, J. D.: Antibacterial activity of bladder surface mucin duplicated in the rabbit bladder by exogenous glycosaminoglycan (sodium pentosanpolysulfate). Infect. Immun., 27: 876, 1980. 8. Parsons, C. L., Schmidt, J. D. and Pollen, J. J.: Successful treatment of interstitial cystitis with sodium pentosanpolysulfate. J. Urol., 130: 51, 1983. 9. Walsh, A.: Interstitial cystitis. In: Campbell's Urology, 4th ed. Edited by J. H. Harrison, R. F. Gittes, A. D. Perlmutter, T. A. Stamey and P. C. Walsh. Philadelphia: W. B. Saunders Co., vol. 1, sect. IV, chapt. 19, p. 633, 1978. 10. Wishard, W. N., Jr., Nourse, M. H. and Mertz, J. H. 0.: Use of clorpactin WCS 90 for relief of symptoms due to interstitial cystitis. J. Urol., 77: 420, 1957. 11. Pool, T. L. and Rives, H. F.: Interstitial cystitis: treatment with
silver nitrate. J. Urol., 51: 520, 1944. 12. Stewart, B. H. and Shirley, S. W.: Further experience with intravesical dimethyl sulfoxide in the treatment of interstitial cystitis. J. Urol., 116: 36, 1976. 13. Fowler, J. E., Jr.: Prospective study of intravesical dimethyl sulfoxide in treatment of suspected early interstitial cystitis. Urology, 18: 21, 1981. 14. Gregor, H. P.: Anticoagulant activity of sulfonate polymers and copolymers. In: Polymer Science and Technology. New York: Plenum Press, vol. 5, p. 51, 1975. 15. Gryte, C. C. and Gregor, H. P.: Poly-(styrene sulfonic acid)-poly(vinylidene fluoride) interpolymer ion-exchange membranes. I. Preparation and characterization. J. Polymer Sci., part A-2, Polymer Physics Edition, 14: 1839, 1976. 16. Gregor, H.P.: Fixed charge ultrafiltration membranes. In: Charged Gels and Membranes, Part 1. Edited by E. Selegny. Holland: D. Reidel, p. 235, 1976. 17. Gill, W. B., Ruggiero, K. and Straus, F. H., II: Crystallization studies in a urothelial-lined living test tube (the catheterized female rat bladder). I. Calcium oxalate crystal adhesion to the chemically injured rat bladder. Invest. Urol., 17: 259, 1980. 18. Gill, W. B., Jones, K. W. and Ruggiero, K. J.: Protective effects of heparin and other sulfated glycosaminoglycans on crystal adhesion to injured urothelium. J. Urol., 127: 152, 1982.