Intravesical suplatast tosilate (IPD-1151T) inhibits experimental bladder inflammation

PURPOSE: Interstitial cystitis is a painful bladder disease characterized by urgency, frequency and variable inflammation but there is no curative therapy. Suplatast tosilate (IPD-1151T) is an immunoregulatory compound that decreases interstitial cystitis symptoms but to our knowledge its mechanism of action is unknown. We investigated the effect of intravesical IPD-1151T on mediator release from bladder explants in experimental cystitis. MATERIALS AND METHODS: A catheter was inserted into the bladder of female mice. After urine was emptied normal saline, carbachol (100 nM) or lipopolysaccharide (10 mg/ml) was introduced with or without 10-minute pretreatment with IPD-1151T. Urine was removed after 45 minutes for histamine and tumor necrosis factor-alpha assays. The bladder was removed after 4 hours, minced into 1 mm2 pieces and cultured with or without triggers overnight for mediator release. The effect of IPD-1151T was also tested on rat skin vascular permeability as well as on purified rat peritoneal mast cells and human cord blood derived mast cells. RESULTS: Carbachol significantly increased histamine release in urine (61.3% in 8 preparations, p<0.05) but not in explant medium. IPD-1151T inhibited this effect by 77%. Lipopolysaccharide induced a 350% urine histamine increase in 9 preparations (p<0.05) and a 300% tumor necrosis factor-alpha increase in explant medium. IPD-1151T inhibited the lipopolysaccharide induced medium tumor necrosis factor-alpha increase by 95% in 5 preparations (p<0.05). IPD-1151T did not inhibit rat skin vascular permeability or purified rat peritoneal mast cell activation by compound 48/80 or human cord blood derived mast cells by anti-IgE. CONCLUSIONS: IPD-1151T inhibits bladder release of histamine and tumor necrosis factor-alpha through a mechanism that does not appear to involve direct mast cell inhibition. These findings may justify a beneficial effect of IPD-1151T in interstitial cystitis.     

Improvement of interstitial cystitis symptoms and problems that developed during treatment with oral IPD-1151T

PURPOSE: We examined the efficacy of Suplatast Tosilatedouble dagger (IPD-1151T), a new immunoregulator that suppresses helper T cell mediated allergic responses, including IgE production and eosinophilic inflammation for treating patients with interstitial cystitis. MATERIALS AND METHODS: A total of 14 women (average age 43.7 years) with interstitial cystitis, which was nonulcerative in 13 and ulcerative in 1, were treated with 300 mg. IPD-1151T orally daily for 12 months. All patients received laboratory assessments, including hematology (eosinophils and CD20 positive cells) and serum chemistry (IgE, and interleukin-4 (IL-4) and 5, and immunohistochemical analyses of urine leukocytes (CD45RO positive cells as a T cell marker) before treatment. These parameters were also measured 4 and 12 months after continuous treatment. The voiding chart, and interstitial cystitis symptom and problem indexes were evaluated before and after IPD-1151T treatment. RESULTS: IPD-1151T treatment for 1 year resulted in a significantly increased bladder capacity and decreased symptoms, such as urinary urgency, frequency and lower abdominal pain, in patients with nonulcerative interstitial cystitis. These effects also correlated with a reduction in blood eosinophils, CD20 positive cells and IgE, and urine CD45RO positive memory T cells. No major side effects were observed. CONCLUSIONS: Our study suggests that immunological responses are involved in the development of interstitial cystitis symptoms. IPD-1151T could be a new oral agent for treatment of voiding symptoms and bladder pain in patients with interstitial cystitis.     

The bladder acellular matrix graft in a rat chemical cystitis model: functional and histologic evaluation

PURPOSE: We investigated the feasibility of augmentation in a diseased bladder with a bladder acellular matrix graft. MATERIALS AND METHODS: In 50 female Sprague-Dawley rats chemical cystitis was induced by intravesical instillation of HCl repeated monthly to maintain chronic inflammation. Urodynamic studies were performed in all rats 1 week after the induction of chemical cystitis and repeated at sacrifice. The 29 rats in the experimental group underwent partial cystectomy (50% or greater), followed by bladder acellular matrix graft augmentation, while the 21 controls underwent monthly HCl instillation only. The rats were sacrificed at 2 weeks, 1, 2 and 3 months, respectively. The bladder was removed and examined for histological changes. RESULTS: Urodynamic studies showed that bladder capacity and compliance were significantly higher in the grafted than in the control group (p = 0.008 and 0.006, respectively, at 3 months). Histological studies revealed urothelial and smooth muscle regeneration within the bladder acellular matrix graft at 1 month and nerve regeneration at 3. The number of mast cells was significantly lower in the grafted region than in the host bladder of all grafted rats (p <0.001). CONCLUSIONS: In this rat chemical cystitis model bladder augmentation with a bladder acellular matrix graft led to functional and histological improvement over diseased host bladder.     

Neuromodulation reduces urinary frequency in rats with hydrochloric acid-induced cystitis

OBJECTIVE: To evaluate the effect of sacral neuromodulation on interstitial cystitis (IC) and determine the underlying mechanism of neuromodulation in the treatment of IC. Materials and methods Twenty Sprague-Dawley rats (body weight 220-250 g) were randomly divided into four equal groups; normal controls, a sham treatment (IC induced by 0.4 mol/L HCl, + saline), a second sham treatment (HCl-induced IC + acetic acid) and a stimulated group (HCl-induced IC + acetic acid, with electrical stimulation). In the last group bilateral electrodes were implanted into the S1 dorsal foramina and electrical stimulation applied for 8 h/day for 3 weeks. Acetic acid was instilled into the bladder to induce c-fos expression. After 3 weeks the rats were perfused with 4% paraformaldehyde, spinal segments dissected out and an immunocytochemical method used to stain the segments for fos protein encoded byc-fos. RESULTS: The mean (SEM) micturition frequency (voids/17 h) in the sham groups increased from 10.8 (2.7) to 23.4 (3.4) 3 weeks after the intravesical instillation of HCl. The micturition frequency in the stimulated group, at 16.2 (2.7), was significantly less than in the sham group (P = 0.04) after electrical stimulation for 3 weeks. There was no significant difference in the mean (SEM) number of fos-positive neurones in the L6 spinal cord segment between the stimulated and the sham + acetic acid group, at 43.6 (9.4) and 35.8 (7.8) cells/section, respectively (P = 0.32). CONCLUSIONS: In rats with HCl-induced cystitis, electrical stimulation reduced the micturition frequency, but not by inhibiting afferent c-fibre activity.     

The effect of chronic inflammatory condition of the bladder and estrogen replacement therapy on bladder functions and histology in surgically menopause and chronic cystitis induced rats

AIMS: We investigated the effect of chronic inflammatory condition of the bladder and estrogen replacement therapy on bladder function and histological changes in surgically menopause and chronic cystitis induced rats. METHODS: The study included 36 female Sprague-Dawley rats, divided into five groups. After bilateral ovariectomy, chronic cystitis was induced by intravesical instillation of HCl, and then group 1 (n = 8) received nasal estrogen, and group 2 (n = 8) received oral estrogen replacement therapy. Group 3 (n = 7) underwent ovariectomy and chronic cystitis, but no replacement therapy. Group 4 (n = 7) had only ovariectomy. Group 5 (n = 6) was taken as sham group. The rats were sacrificed after 60 days, and cystometric study and histological findings were compared among the groups. RESULTS: The mean maximal bladder capacity and compliance revealed significant decreases in group 3 and 4 compared with group 5, and significant increases in group 1 and 2 compared with group 3. Histological findings showed significant increases in the mast cells and leukocyte infiltration of group 3 and 4 compared with group 5, and significant decreases in the mast cells and leukocyte infiltration of group 1 and 2 compared with group 3. CONCLUSIONS: This experimental menopause and chronic cystitis model showed that bladder function and histology might deteriorate much more with chronic cystitis in postmenopausal period. This is the first study in the literature to report that chronic inflammatory bladder occurring after menopause can be improved by estrogen replacement therapy.     

The effect of tamoxifen on bladder functions and histology, and the role of estrogen receptor beta in a rat chemical cystitis model

AIMS: The purpose of this study was to investigate the effect of tamoxifen citrate on bladder functions and histology, and also to investigate the role of estrogen receptor beta (ER beta) in a rat chemical cystitis model. METHODS: The study included 37 female Sprague-Dawley rats. Chemical cystitis was induced by intravesical instillation of hydrochloric acid in 32 rats, and the treatment group (n = 15) received daily 0.4 mg/kg of tamoxifen citrate with orogastric tube, and the control group (n = 17) received no treatment. The sham group consisted of five rats having no acid instillation and no treatment. Cystometric studies were performed in all rats at the beginning and end of the experiment. The rats were euthanized at 2 months. The bladders were removed and examined histologically for mast cells, inflammatory cells, and ER beta. RESULTS: The mean maximal bladder volume increased by 73.6% +/- 25.2 in the treatment group and decreased by 7.2% +/- 10.8 in the control group, revealing a significant difference (P = 0.007). The mean bladder compliance increased by 81.2% +/- 25.2 in the treatment group and decreased by 4.8% +/- 12.7 in the control group, revealing a significant difference between the two groups (P = 0.005). ER beta positive cells were significantly lower in the bladders with chronic cystitis than in the sham group (P = 0.038). CONCLUSIONS: Tamoxifen citrate may be an alternative choice, as easy, to other treatment options in the treatment of chronic inflammatory condition to improve deteriorated bladder function. In addition, ER beta may have a role on chronic bladder inflammation in a rat chemical cystitis model.     

Botulinum toxin type A may improve bladder function in a rat chemical cystitis model

The purpose of this study was to investigate the effect of botulinum toxin type A on bladder function and histology in a rat chemical cystitis model. The study included 41 female Sprague-Dawley rats with chemical cystitis induced by intravesical instillation of hydrochloric acid. The acid instillation was repeated monthly to maintain chronic inflammation. The treatment group (n=21) received 2-3 units of botulinum toxin type A injected into the bladder detrusor at the 3, 6, 9 and 12 o'clock positions, and the control group (n=20) underwent saline injection into the bladder detrusor at the same positions. Urodynamic studies were performed in all rats before the treatment and at death. The rats were killed at 1 week, 2 weeks, 1 month and 2 months after treatment. The bladders were removed and examined histologically for mast cells and inflammatory changes. The cystometric findings showed that, at the beginning and end of the experiment, the increases in the maximum bladder capacity and compliance were significantly higher in the treatment group than in the control group (P=0.000 and P=0.025, respectively). The histological studies revealed similar mast cell counts and leukocyte infiltration for the treatment and control groups. In conclusion, in this rat chemical cystitis model, botulinum toxin type A injected into the bladder detrusor led to a functional improvement. Thus, botulinum toxin type A injection may be an alternative, minimally invasive choice to other surgical treatment options in the treatment of a chronic inflammatory condition to improve deteriorated bladder function.     

Bladder wall injection of mesenchymal stem cells ameliorates bladder inflammation,overactivity, and nociception in a chemically induced interstitial cystitis-like rat model

Introduction and hypothesis

We investigated the effects of bladder wall injection of mesenchymal stem cells (MSCs) on bladder tissues, function, and nociceptive behavior in a chemically induced interstitial cystitis-like rat model.

Methods

Chemical cystitis of female rats was induced by intravesical instillation of 0.1 N hydrochloride (HCl) once a week for 2 weeks. Bladders were harvested 1, 2, 3, and 4 weeks after the second application for histological examination. Adipose-derived MSCs (HCl?+?MSCs) or phosphate-buffered saline (HCl?+?PBS) was injected into the bladder wall at the time of the second application of HCl. Histological examination, nociceptive behavior, and cystometrograms were evaluated 2 weeks after the injection compared with controls, which received instillation and injection of PBS into the bladder (sham + PBS).

Results

The number of mast cells and expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) were significantly increased at 1 and 2 weeks, and expression of collagen fibers was significantly increased from 2–4 weeks after the second application of HCl. Significantly increased nociceptive behavior, number of mast cells, expression of TNF-α, TGF-β, and collagen fibers were observed in HCl?+?PBS compared with sham?+?PBS, whereas these changes were significantly decreased in HCl?+?MSCs compared with HCl?+?PBS. In addition, bladder capacity and voiding threshold pressures were significantly decreased in HCl?+?PBS but not in HCl?+?MSCs compared with sham?+?PBS.

Conclusions

The results suggest that bladder injection of MSCs ameliorates inflammation and fibrosis in bladder tissues, bladder overactivity, and nociception in a rat model of chemically induced cystitis.

     

Possible pathophysiology of ketamine‐related cystitis and associated treatment strategies

Ketamine‐related cystitis is characterized by ketamine‐induced urinary frequency and bladder pain. It has become a serious problem in recent years. The most typical grossly pathological bladder change with ketamine related cystitis is a contracted bladder and bladder wall thickening. Ulcerative cystitis with an easily bleeding mucosa is a common cystoscopic finding. Microscopically, the urothelium is denuded and is infiltrated by inflammatory cells, such as mast cells and eosinophils. The pathogenesis of ketamine‐related cystitis is complicated and involves many different pathways. Past evidence suggests a direct toxic effect, bladder barrier dysfunction, neurogenic inflammation, immunoglobulin‐E‐mediated inflammation, overexpression of carcinogenic genes, abnormal apoptosis and nitric oxide synthase‐mediated inflammation contribute to the pathogenesis of ketamine‐related cystitis. The first step to managing ketamine‐related cystitis is always asking patients to cease ketamine. Medical treatment might be helpful in patients with early ketamine‐related cystitis and abstinence from ketamine. Several case studies showed that the intravesical installation of hyaluronic acid and intravesical injection of botulinum toxin type A were effective for symptom relief in selected patients. For patients with irreversible pathological change, such as contracted bladder, augmentation enterocystoplasty might be the only solution to increase bladder capacity and relieve intractable bladder pain.     

Intravesical therapy of heparin and lidocaine for interstitial cystitis : a case report

Interstitial cystitis (IC) is a chronic inflammatory condition of the urinary bladder, and its treatment has many uncertainties. We report a case of IC treated with intravesical instillation of heparin and alkalized lidocaine. A 64-year-old woman presented with urinary frequency and urgency with suprapubic pain. She underwent intravesical treatment with combined heparin and alkalinized lidocaine for IC, since prior medical treatments (imipramine, solifenacin, suplatast tosilate, and kampo extracts) and hydrodistention of bladder had little or no effect on her symptoms. A 50 ml solution containing 20,000 units of heparin, 200 mg of lidocaine and 7% sodium bicarbonate was administered intravesically twice a week for 12 months. The O'Leary-Sant IC symptom index score and IC problem index score improved from 20 to 8 and from 16 to 8, respectively, and her bladder capacity increased from 90 ml to 300 ml. Intravesical instillation of combined heparin and lidocaine was useful in the treatment of IC.     

间质性膀胱炎大鼠膀胱ICAM-1与功能膀胱容量的关系

目的探索间质性膀胱炎(IC)大鼠膀胱组织细胞间粘附分子(ICAM-1)水平与膀胱容量之间的关系。方法雌性SD大鼠分为正常对照、IC模型和透明质酸(HA)治疗3组,每组10只。以腹腔注射环磷酰胺联合膀胱灌注鱼精蛋白和脂多糖制作IC模型(IC模型组),模型鼠膀胱灌注HA进行治疗者为HA组。检测各组的平均排尿量和24h总尿量,以及膀胱组织肥大细胞浸润数、ICAM-1和肿瘤坏死因子α(TNF-α)水平。结果 IC模型组的平均排尿量显著小于正常大鼠(1.10mL vs.1.88mL,P0.001)和HA治疗组(1.30mL vs.1.10mL,P=0.009),而3组的24h总尿量无显著差异。IC模型大鼠无论是肥大细胞浸润数目还是ICAM-1、TNF-α含量,均较正常对照有极显著升高(P均0.001)。该3项指标在HA组有显著减少。相关分析显示,平均尿量与ICAM-1水平呈显著负相关(r=-0.725,P0.001),而与肥大细胞浸润数和组织TNF-α含量无显著相关性。结论 SD大鼠IC模型膀胱组织ICAM-1水平与功能性膀胱容量之间存在密切相关性,降低ICAM-1可有效增加功能性膀胱容量。ICAM-1有望成为IC治疗的观测指标。     

Eosinophilic cystitis induced by bacillus Calmette-Guerin (BCG) intravesical instillation

Eosinophilic cystitis is a rare and uncommon inflammatory bladder disease, in which the pathophysiology is unclear; only a few cases of such disease induced by intravesical instillations have been described. We report a case of eosinophilic cystitis after intravesical bacillus Calmette-Guerin (BCG) instillation for nonmuscle-invasive transitional cell carcinoma of the bladder. To our knowledge, this report is the first case of eosinophilic cystitis induced by intravesical BCG therapy.     

Role of liposome in treatment of overactive bladder and interstitial cystitis

Intravesical (local) therapy of agents has been effective in delaying or preventing recurrence of superficial bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) and overactive bladder without systemic side effects. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core. They can incorporate drug molecules, both hydrophilic and hydrophobic, and show greater uptake into cells via endocytosis. Intravesical liposomes have therapeutic effects on IC/PBS patients, mainly because of their ability to form a protective lipid film on the urothelial surface. Recent studies have shown the sustained efficacy and safety of intravesical instillation of botulinum toxin formulated with liposomes (lipo-BoNT) for the treatment of refractory overactive bladder This review considers the current status of intravesical liposomes or liposomal mediated drug delivery for the treatment of IC/PBS and overactive bladder.     

Urine eosinophil cationic protein in painful bladder disease

Urine eosinophil cationic protein (U-ECP), blood eosinophils and eosinophils in bladder biopsy specimens were studied in 30 patients with painful bladder disease (15 with detrusor mastocytosis, i.e. interstitial cystitis (IC) (greater than or equal to 28 mast cells/mm2 in the detrusor muscle) and 15 patients without detrusor mastocytosis). In patients with IC the median concentration of U-ECP was 140 arbitrary u/l versus 14 arb. u/l in the remaining patients (P less than 0.001). The mean peripheral leukocyte count was significantly lower in the IC group (P less than 0.05). Tissue infiltration with eosinophils was found in 43% of the bladder biopsies from patients with IC compared with 4% of the biopsies in the remaining patients (P less than 0.05). A negative correlation between peripheral eosinophils and U-ECP was found in the patients with IC (r = 0.52, P less than 0.05). These results suggest that eosinophils are attracted to the inflammatory site in the bladder wall where ECP is released. Eosinophils thus seem to participate actively in the inflammatory process. U-ECP seems to provide valuable diagnostic information when diagnosing IC in patients with painful bladder disease. It is suggested that ECP might be involved in the process of tissue destruction in IC.     

Intravesical therapy for lower urinary tract symptoms

Intravesical (local) therapy for diseases emanating from the bladder is similar to the commonplace management of ocular diseases using eyedrops. The existing intravesical therapy involves administering dosage forms directly into the bladder (through a catheter). This mode of treatment is routine in the bladder cancer by instillation of bacillus Calmette–Guérin to provoke the body's own natural defenses against invasion by proliferating cancer cells in the bladder. Although convenient, the conventional routes of administration for treating diseases such as interstitial cystitis/painful bladder syndrome (IC/PBS) and overactive bladder (OAB) are less acceptable to patients owing to side effects, which may further exacerbate the disease symptoms. Intravesical therapy has demonstrated varying degrees of efficacy and safety in treating IC/PBS and OAB. In recent years, intravesical delivery of biotechnological products including neurotoxins using a liposome platform demonstrated immense promise for lower urinary tract symptoms. This review considers the current status of intravesical therapy in lower urinary tract diseases with special attention to novel drug-delivery systems.     

Intravesical instillation of resiniferatoxin for the patients with interstitial cystitis

Although hydrodistention of the bladder is accepted as the initial treatment for patients with interstitial cystitis (IC), second-line treatment for worsening symptoms is not concretely established. Resiniferatoxin (RTX) desensitizes bladder afferent c-fibers and its intravesical instillation is effective for patients with detrusor overactivity. We studied the clinical relevance of intravesical treatment with RTX for patients with IC. The treatment was performed for 3 patients with incomplete improvement after hydrodistention. All 3 patients were free of bladder pain posttreatment and had slight improvement of the maximum voided volume. Though RTX treatment requires general anesthesia against severe bladder pain it is effective for selected patients with interstitial cystitis and can be potentially used as one of the treatment options.     

Does interstitial cystitis urine include possible factors effecting the nociceptive system of the spinal cord?

INTRODUCTION: We investigated the effect of interstitial cystitis (IC) urine on bladder layers and nociceptive centers in the spinal cord with determination of nerve growth factor (NGF), neuronal nitric oxide synthase (nNOS) and c-fos expressions. MATERIAL AND METHODS: Female rats were instilled into the bladder IC urine (Group-IC), normal urine (Group-NU) and saline (Group-S). NGF, nNOS and c-fos activity were determined in the L6-S1 medulla spinalis with identification of mast cell and NGF activity on bladder layers. RESULTS: There was more NGF expression cell density in the bladder wall that was determined immunohistochemically in control and IC urine instillation groups than Group-S. While there was no difference in nNOS, NGF and c-fos activity between spinal cord regions except the lateral dorsal horn of the L6 section, localization of activities was different in Group-IC. CONCLUSIONS: The characteristics of the bladder wall and its nociceptive afferents after human urine instillation of some toxic compounds might be causative factors for IC. However, it is barely hard to conclude that different toxic compounds should be causative factors in IC urine in the pathogenesis of IC.     

MAST CELLS MEDIATE THE SEVERITY OF EXPERIMENTAL CYSTITIS IN MICE

PURPOSE: We hypothesized that experimental cystitis induced by substance P (SP) or E. coli lipopolysaccharide (LPS) would be less severe in mice rendered mast cell deficient by genetic manipulation. MATERIALS AND METHODS: Two strains of mast-cell deficient mice (WBB6F1- kitW/kitW-v or kitW/kitW-v and WCB6F1-Sl/Sld or Sl/Sld) and their congenic, normal (+/+) counterparts were used. Cystitis was induced in female mice by intravenous injection of SP (0.1 ml.; 10(-6) M) or E. coli LPS (0.1 ml.; 2 mg./ml.), and inflammation was assessed by Evans blue dye extravasation. In a separate group of kitW/kitW-v and congenic normal mice, cystitis was induced by intravesical infusion of SP (0.05 ml.; 10(-5) M) or E. coli LPS (0.05 ml.; 100 microg./ml.) and compared with intravesical pyrogen-free saline (0.05 ml.; 0.9%). Severity of cystitis was determined by histological evaluation of the bladder wall 24 hours after intravesical infusions. RESULTS: Intravenous SP or LPS stimulated increased plasma extravasation in congenic normal mice but not in mast cell-deficient mice. Intravesical SP or LPS resulted in increased edema, leukocytic infiltration, and hemorrhage within the bladder wall in congenic normal mice, but the only histological evidence of inflammation in the bladders of kitW/kitW-v mice was increased hemorrhage in response to LPS. CONCLUSIONS: This study indicates that mast cells modulate the inflammatory response of the bladder to SP and LPS in mice. Although clinical trials of the use of antihistamines to treat or prevent cystitis have not been successful, these results suggest that therapies directed toward preventing mast cell activation may yet prove effective in treating cystitis.     

Anesthetic management of patients with interstitial cystitis during intravesical resiniferatoxin therapy

The management of patient with interstitial cystitis (IC) remains a challenge because no single agent has proven effective. IC is a chronic sterile inflammatory disease of the bladder of unknown etiology characterized by urinary frequency, urgenecy, nocturia and lower abdominal pain. We experienced anesthetic management of five patients with IC during intravesical resiniferatoxin (RTX) therapy. RTX is associated with irritative urinary symptom during bladder instillation. The patients with IC had bladder instillation with 100 ml of 10(-8) M RTX solution for 30 min. The first patient received combined spinal-epidural anesthesia (CSEA), and the others general anesthesia. The patient with regional anesthesia had no critical troubles related to circulatory status during the procedure, but increases of blood pressure after instillation of RTX were observed in two patients receiving general anesthesia. In spite of the increase in blood pressure during general anesthesia, regional anesthesia should not be used, because the effect of RTX on the spinal cord has to be maintained.     

Comparison of intravenous and intravesical administration of chloro-aluminum sulfonated phthalocyanine for photodynamic treatment in a rat bladder cancer model.

Photodynamic therapy is an experimental treatment of superficial bladder tumors. Photofrin, a mixture of porphyrins, is the only photosensitizer in clinical use in the U.S.A. and its major side effect is prolonged cutaneous phototoxicity. In order to circumvent this problem of phototoxicity, new photosensitizers are being examined. Cutaneous phototoxicity may also be minimized by local administration of photosensitizer. Therefore, in this study, we investigated the photosensitizer chloro-aluminum sulfonated phthalocyanine (CASPc) in vivo in a rat bladder carcinoma model, and compared two different routes of CASPc administration. AY-27 rat bladder carcinoma cells were transplanted into rat bladders. Eight days after tumor transplantation the biodistribution of CASPc in bladder, skin, muscle and bladder tumor was determined by fluorescence measurements after dye extraction. Photosensitizer administered by intravenous injection and intravesical instillation, were compared. The concentration of CASPc in bladder and bladder tumor after intravenous injection and intravesical instillation was similar. The ratio of dye uptake between tumor and normal bladder after either administration was approximately two. Although no systemic absorption of the photosensitizer was observed after intravesical instillation, there was no reduction in tumor uptake or in the ratio between tumor to normal surrounding tissue. Therefore, no systemic side effects of skin phototoxicity are expected upon intravesical instillation. The microscopic biodistribution of CASPc after intravenous injection and intravesical instillation was also compared. After intravenous injection, the photosensitizer was distributed within the whole tumor with increased fluorescence around the microvasculature. In the normal bladder wall, weak fluorescence was seen in the area of the vasculature in the submucosa and the muscularis. After intravesical instillation, strong fluorescence was detected only at the tumor surface and in normal urothelium; no fluorescence was found in other areas of the tumor or in submucosa or muscularis. A comparison of the photodynamic treatment of model bladder tumors showed that tumor destruction after either method was similar but that there were less side effects to normal bladder wall after intravesical instillation of the CASPc. Intravesical administration of photosensitizers may, therefore, be a viable alternative to intravenous injection with potential for reduced systemic and normal tissue toxicity.