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PubMed1992

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.

Administration, Intravesical↗
PubMed2002

Comparison of normal piglet bladder damage after PDT with oral or intravesical administration of ALA.

5-Aminolaevulinic-acid (ALA) can be used as an alternative drug in photodynamic therapy of the bladder, since the selective formation of protoporphyrin IX (PpIX) in the tumour and the virtual absence of induced skin photosensitivity are theoretically advantageous for clinical use. A preclinical study was performed, using an in vivo normal piglet bladder model, in order to determine the maximum drug and light doses for reversible tissue damage. Various ALA doses were administered either orally or instilled in the bladder and different radiant exposures were applied. Bladder biopsies were taken at regular intervals and tissue damage was investigated histologically. After oral ALA-administration the PpIX concentration was determined in plasma, erythrocytes and various tissues. In the case of oral administration, reversible bladder damage was observed using 60-75 mg/kg ALA combined with a radiant exposure of 100 J/cm(2) (direct radiant exposure plus scattered 632 nm light) 5-7 h later. For an oral ALA dose of up to 150 mg/kg, the maximum PpIX concentration is reached at approximately 5 h following administration and in neither skin nor bladder tissue is PpIX present at 10-11 h after administration. This ALA dose combined with a radiant exposure of 200 J/cm(2) produces irreversible bladder damage (extensive necrosis and ulceration). In the case of intravesical instillation for 4-4.75 h, an ALA dose of 2.5 g in 50 ml phosphate buffered saline and a radiant exposure of 100 J/cm(2) are still too high to obtain reversible tissue damage; at this dose one of the 13 pigs developed a shrunken bladder with a fibrotic, thickened bladder wall. These drug and light combinations reported above should be regarded as upper limits in pigs and can serve as an indication for the toxicity of the treatment in a clinical setting.

Administration, Intravesical↗
PubMed2000

Targeting superficial bladder cancer by the intravesical administration of copper-67-labeled anti-MUC1 mucin monoclonal antibody C595.

PURPOSE: More effective intravesical agents are required to limit the recurrence and progression of superficial bladder cancer. This study assessed the ability of copper-67 ((67)Cu)-C595 murine antimucin monoclonal antibody to bind selectively to superficial bladder tumors when administered intravesically, with a view to its development for therapy. PATIENTS AND METHODS: Approximately 20 MBq of (67)Cu-C595 monoclonal antibody was administered intravesically to 16 patients with a clinical indication of superficial bladder cancer. After 1 hour, the bladder was drained and irrigated. Tissue uptake was assessed by imaging and by the assay of tumor and normal tissues obtained by endoscopic resection. RESULTS: Tumor was correctly identified in the images of 12 of 15 patients who were subsequently found to have tumors. Assay of biopsy samples at 2 hours showed a mean tumor uptake of 59.4% of the injected dose per kilogram (SD = 48.0), with a tumor-to-normal tissue ratio of 14.6:1 (SD = 20). After 24 hours (n = 5), this decreased to 4.3% of the injected dose per kilogram (SD = 2.9), with a tumor-to-normal tissue ratio of 1.8:1 (SD = 0.8). CONCLUSION: This study indicates a promising method for the treatment of superficial bladder cancer. Although the mean initial tumor uptake was high, effective therapy of bladder tumors will require an increased retention of the cytotoxic radionuclide in tumor tissue.

Administration, Intravesical↗
PubMedDate not supplied

[The intravesical administration of BCG vaccine in treating recurrent superficial bladder cancer].

The authors consider general immunological effects of intravesical BCG vaccine as an independent method of immunotherapy of superficial cancer of the bladder (CB). 27 patients (15 males and 12 females, mean age 57 years) with a recurrence of superficial CB (T1-2N0M0) were treated. The patients had undergone transurethral or transvesical bladder resection and combined therapy. Intravesical immunotherapy of CB recurrence with BCG vaccine induced persistent changes in the immune system: stimulate lymphocyte activity and phagocytic activity of neutrophils, T-cell function, normalizes function of endogenic suppressors, increases the amount of IgM and CIC. Repeat courses of the vaccine maintain the above immunological effects for a long time.

Administration, Intravesical↗
PubMedDate not supplied

Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder.

Superficial transitional cell carcinoma (STCC) of the bladder is usually managed with intravesical bacille Calmette-Guerin. Recombinant human interleukin-12 (rhIL-12) is a heterodimeric cytokine that induces T-cell and natural killer cell proliferation/activation and production of IFNgamma. It has demonstrated preclinical in vivo bladder antitumor activity and no systemic toxicity. This phase 1 study evaluated intravesical rhIL-12 administration in patients with STCC (Tis, Ta, or T1) who had failed at least one prior intravesical therapy or had at least two recurrences of low-grade tumors. Eligible patients had adequate hematologic, renal, and hepatic function and Karnofsky performance status at least 70%. Cohorts of three patients received 5, 20, 50, 100, and 200 microg rhIL-12 (treated n = 15). Each patient received intravesical rhIL-12 weekly for 6 weeks, with a 2-hour bladder dwell. No patient experienced moderate, severe, or life-threatening systemic toxicity. Treatment-related adverse events included dysuria, urinary frequency, urinary urgency, asthenia, pain, hematuria, bladder spasms, and chills. Specific AE incidences were not dose-related. Among 12 patients without visible pretreatment lesions, 7 remained disease-free and 5 experienced recurrence of STCC within the 4-week follow-up period. Three patients with pretreatment Tis or Ta/T1 lesions had persistent disease at posttreatment follow-up. No patients with persistent tumor manifested antitumor response to rhIL-12. Two-hour dwell urine samples and 24- to 30-hour postdose serum samples showed negligible induction of IFNgamma. In summary, intravesical rhIL-12 was well tolerated by patients with recurrent STCC but showed no clinically relevant evidence of antitumor or immunologic effects.

Administration, Intravesical↗
PubMed1995

Effects and systemic uptake of the new mitomycin C analogue KW-2149 in beagle dogs after intravesical administration.

The present study was designed to evaluate the local effects of the new mitomycin C analogue KW-2149 after intravesical instillation, together with its penetration into the systemic circulation in healthy beagle dogs. Two reference dogs were treated with two instillations of mitomycin C (30 mg in 30 ml phosphate buffer). Four dogs were given two, three, four and six instillations, respectively, of KW-2149 (60 mg in 30 ml phosphate buffer). KW-2149 concentrations measured in the systemic circulation were very low and were frequently found to be below the limit of determination. The number of instillations had no influence on the KW-2149 concentrations measured in the systemic circulation. Blood analysis showed no systemic toxicity. The histopathological findings in the bladder were comparable in both groups. The number of instillations had no influence on the severity of the lesions found in the bladder wall. On the basis of its in vitro activity KW-2149 can be regarded as a promising agent for intravesical treatment of superficial bladder cancer.

Administration, Intravesical↗
PubMed2006

Determination of the bioavailability of [14C]-hexaminolevulinate using accelerator mass spectrometry after intravesical administration to human volunteers.

Hexaminolevulinate (HAL) is a diagnostic agent that allows the visualization of tumor tissue in the bladder by fluorescence cystoscopy. It is administered intravesically via a catheter for 1 hour, followed by blue light bladder inspection to induce selective red tumor fluorescence. Hexaminolevulinate should ideally be confined to the bladder only, but it is likely that some absorption occurs during administration, and therefore the systemic bioavailability is of interest. The bioavailability of HAL was determined by intravesical and intravenous administration of [14C]-HAL hydrochloride to 8 human volunteers. To reduce the radiation dose as low as possible, the ultrasensitive analytical technique of accelerator mass spectrometry was used to measure [14C]-HAL. The bioavailability of [14C]-HAL after intravesical and intravenous administration was determined from the respective area under the curve based on total radioactivity and was determined to be 7% (range, 5%-10%; 90% confidence interval). The systemic absorption of [14C]-HAL after intravesical administration is low and supports previous clinical experience with HAL showing no systemic side effects.

Administration, Intravesical↗
PubMed2004

Phase II study to investigate the ablative efficacy of intravesical administration of gemcitabine in intermediate-risk superficial bladder cancer (SBC).

OBJECTIVE: Phase I studies have so far demonstrated that intravesical Gemcitabine up to a 40 mg/ml concentration is well tolerated and has a substantial ablative activity on high-risk BCG refractory SBC. New treatment options are needed for intermediate-risk SBC recurring after conventional intravesical treatments. The purpose of the present study was to investigate the ablative efficacy of intravesical Gemcitabine on intermediate-risk SBC. METHODS: The study was designed as a two-stage phase II trial, with a sample size of 39 patients. The efficacy of intravesical Gemcitabine at a concentration of 40 mg/ml (2000 mg in 50 ml saline solution) administered weekly for 6 weeks was assessed on a single marker tumour left in the bladder after a complete TUR of all other lesions. Patients underwent TUR or biopsy at the site of the marker lesion 2 weeks after completion of the treatment. RESULTS: Complete response was observed in 22 out of 39 patients (56%). No progression was observed among the 17 non-responders. Neither systemic nor local side effects generally exceeded grade I toxicity. CONCLUSION: The ablative effect of Gemcitabine produced a higher number of responses than the minimum required by the protocol to indicate a significant probability of drug efficacy. It is worth testing the drug in phase III trials to assess for durability of response.

Administration, Intravesical↗
PubMed2000

The effect of fasting or desmopressin before treatment on the concentration of mitomycin C during intravesical administration.

OBJECTIVE: To evaluate two methods of reducing the urine output during treatment (the most easily manipulated variable) in patients undergoing intravesical instillation with mitomycin C, where the concentration-time curve also depends upon dose, diluent volume, residual urine volume, and drug absorption and degradation. PATIENTS AND METHODS: The study comprised 20 consecutive patients undergoing a course of six weekly instillations of mitomycin C (40 mg in 40 mL for 1 h) for superficial bladder carcinoma. Urine production during treatment was calculated by adding the voided volume and ultrasonographically measured residual urine after treatment, and subtracting 40 mL; the patient's bladder was emptied before instillation. Before the first and second visit the patients were asked to drink normally. Before the third and fourth visit patients fasted for 6 h before treatment. For the fifth and sixth visit the patients had not fasted, but 200 microg of desmopressin was given orally 1 h before instillation. Any urinary side-effects were graded on a four-point scale. RESULTS: There were 17 patients with complete data; one patient failed to take desmopressin, one had detrusor instability and one developed chemical cystitis. The mean (SD) urine production in unprepared patients was 209 (123) mL, which decreased to 143 (80) mL (P = 0.039, t-test) after fasting and 103 (51) mL (P < 0.001) with desmopressin. This equates to a 20% increase in mean intravesical drug concentration with fasting and a 38% increase with desmopressin. Urinary side-effects were graded as mild in each group. CONCLUSION: Unprepared patients produce variable and often substantial volumes of urine during intravesical chemotherapy. There was a significant reduction in urine output after fasting or by administering desmopressin before instillation. These measures increase the area under the concentration-time curve for mitomycin C and potentially increase the efficacy of treatment.

Administration, Intravesical↗
PubMed1994

Effects of sequential intravesical administration of mitomycin C and bacillus Calmette-Guérin on the immune response in the guinea pig bladder.

It has been suggested that intravesical treatment with mitomycin C (MMC) before instillation of bacillus Calmette-Guérin (BCG) improves the antitumor activity of BCG in human bladder cancer. Therefore, we studied the immunological effects of sequential intravesical treatment with MMC and BCG in the guinea pig. Four weekly intravesical instillations with MMC preceded six weekly intravesical BCG instillations. The delayed-type hypersensitivity (DTH) skin reaction evoked by tuberculin purified protein derivative (PPD) in guinea pigs receiving BCG intravesically appeared slightly earlier in animals pretreated intravesically with MMC than in phosphate-buffered saline (PBS)-pretreated animals. However, after completing BCG instillations no differences in DTH reaction were observed between these treatment groups. The extent of the local inflammatory reaction in the bladder wall, as well as the parameters measured in the draining iliacal lymph nodes (i.e., the weight, the number of leukocytes, and the composition of leukocyte subpopulations), did not differ in animals treated with BCG alone or in combination with MMC. A slight increase in the MHC class II expression on the bladder urothelium was shown if MMC and BCG treatment was combined. The adherence of mycobacteria to the bladder wall, measured using 3H-labeled mycobacteria, dit not differ between MMC/BCG- and BCG-treated animals. We conclude that MMC does not enhance the immune response against mycobacteria. Therefore, we hypothesize that a possible increased antitumor activity by the combination of MMC and BCG might be due to separate, rather than synergistic, effects of the drugs, namely a cytostatic effect of MMC on tumor cells and a local immune response in the bladder evoked by BCG.

Administration, Intravesical↗
PubMed1993

Intravesical administration of indium-111-labelled HMFG2 monoclonal antibody in superficial bladder carcinomas.

Tumour-associated HMFG2 monoclonal antibody (MAb) was labelled with indium-111 and administered intravesically to 20 patients with known or suspected superficial bladder carcinoma. The antibody solution was kept in the bladder for 1 hr and was then washed out. Cystoscopy was performed at 2 and 24 hr after instillation. Radioactivity of tumour and normal tissue obtained from the bladder during cystoscopy and cells recovered from urine after the instillation were counted in a gamma-counter. Conventional histology, immunocytochemistry and autoradiography were also performed. Mean uptake at 2 and at 24 hr was higher in tumours than in normal samples. Autoradiography showed selective accumulation of radioactivity in cells which expressed the antigen detected by the HMFG2 MAb. There was no correlation of tumour uptake with the grade of tumour. No radioactivity was found in the blood of patients after the instillation. Based on dosimetric calculations, however, the radiation dose that can be delivered to the tumours is not sufficient to be cytotoxic, possibly due to inadequate penetration and retention by tumour tissue. Nevertheless, the significant difference between antibody uptake by the tumours and that by normal urothelium, observed in our study, allow for the possibility of using this approach therapeutically.

Administration, Intravesical↗
PubMed1999

Effects of intravesical administration of the K+ channel opener, ZD6169, in conscious rats with and without bladder outflow obstruction.

PURPOSE: To investigate the urodynamic effects of the new K(ATP) channel opener, ZD6169, given intravesically, in rats with and without bladder outflow obstruction. MATERIALS AND METHODS: Female, conscious Sprague-Dawley rats, normal or with bladder hypertrophy and overactivity secondary to bladder outflow obstruction, were given ZD6169 intravesically (10 or 100 ng./ml.), and intra-arterially (1 mg./kg.). Continuous cystometry was performed. RESULTS: In normal and obstructed rats, intravesical ZD6169 had similar, dose-dependent effects on bladder function. In obstructed rats, ZD6169 (100 ng./ml.) significantly decreased micturition pressure (17%), and increased bladder capacity (32%), micturition volume (18%), residual volume (145%), and inter-contraction interval (71%). There was a marked decrease in both frequency (40%) and amplitude (43%) of the spontaneous bladder activity. When given intra-arterially in obstructed rats ZD6169 increased bladder capacity (19%) and residual volume (47%) and decreased amplitude (51%), but not frequency, of the spontaneous bladder activity. CONCLUSIONS: In both normal and obstructed rats, intravesical ZD6169, at the investigated doses, significantly affected bladder function. In obstructed rats, the drug markedly reduced bladder overactivity. If the results have clinical validity, intravesical ZD6169 may offer an alternative way of treating bladder overactivity in selected patients.

Administration, Intravesical↗
PubMed1991

Facilitation of reflex micturition by intravesical administration of [beta Ala8]-neurokinin A (4-10), a selective NK-2 tachykinin receptor agonist.

We have determined the ability of [beta Ala8]-NKA(4-10), a selective agonist for NK-2 tachykinin receptors to stimulate micturition in anesthetized rats and guinea-pigs. In both species, the intravesical instillation of the peptide at microM concentrations reduced bladder capacity and residual volume, indicating a facilitatory effect on reflex micturition. At these concentrations, no plasma extravasation was produced as determined by the Evans blue content of the organ. In experiments on the isolated rat or guinea-pig bladder strips, the NK-2 receptor agonist induced powerful contractions. In a in vitro model of the guinea-pig whole bladder the intravesical instillation of the NK-2 agonist facilitated the occurrence of rhythmic contractile activity. It is concluded from these studies that intravenous administration of [beta Ala8]-NKA(4-10) exerts a facilitatory effect on the micturition reflex, presumably involving the ability of the NK-2 receptor agonist to cross the urothelium and stimulate smooth muscle contraction.

Administration, Intravesical↗
PubMed2005

Intravesical administration of small interfering RNA targeting PLK-1 successfully prevents the growth of bladder cancer.

The mainstay in the management of invasive bladder cancer continues to be radical cystectomy. With regard to improvement of quality of life, however, therapies that preserve the bladder are desirable. We investigated the use of intravesical PLK-1 small interfering RNA (siRNA) against bladder cancer. Patients with bladder cancers expressing high levels of PLK-1 have a poor prognosis compared with patients with low expression. Using siRNA/cationic liposomes, the expression of endogenous PLK-1 could be suppressed in bladder cancer cells in a time- and dose-dependent manner. As a consequence, PLK-1 functions were disrupted. Inhibition of bipolar spindle formation, accumulation of cyclin B1, reduced cell proliferation, and induction of apoptosis were observed. In order to determine the efficacy of the siRNA/liposomes in vivo, we established an orthotopic mouse model using a LUC-labeled bladder cancer cell line, UM-UC-3(LUC). PLK-1 siRNA was successfully transfected into the cells, reduced PLK-1 expression, and prevented the growth of bladder cancer in this mouse model. This is the first demonstration, to our knowledge, of inhibition of cancer growth in the murine bladder by intravesical siRNA/cationic liposomes. We believe intravesical siRNA instillation against bladder cancer will be useful as a therapeutic tool.

Administration, Intravesical↗
PubMed2004

Prevention of recurrent bacterial cystitis by intravesical administration of hyaluronic acid: a pilot study.

OBJECTIVES: To assess the effect of bladder instillations of hyaluronic acid (HA) on the rate of recurrence of urinary tract infection (UTI). PATIENTS AND METHODS: Forty women (mean age 35 years) with a history of recurrent UTI received intravesical instillations of HA (40 mg in 50 mL phosphate-buffered saline) once weekly for 4 weeks then once monthly for 4 months. The UTI status was assessed over a prospective follow-up of 12.4 months and compared with the rates of UTI before instillation, determined by a retrospective review of patient charts covering 15.8 months. RESULTS: After HA treatment no patients had a UTI during the 5-month treatment phase and 28 (70%) were recurrence-free at the end of the follow-up. The mean (sd) rate of UTI per patient-year was 4.3 (1.55) before treatment and 0.3 (0.55) afterward (P < 0.001). The median time to recurrence after HA treatment was 498 days, compared with 96 days beforehand (P < 0.001). The tolerability was excellent, as side-effects were limited to nine patients who reported mild bladder irritation; no patient interrupted the treatment. CONCLUSIONS: In this preliminary study, bladder instillations of HA had a significant effect on the rate of UTI in women with a history of recurrent UTIs. The bladder instillation of HA is an acceptable and promising therapeutic alternative in patients with recurrent UTI. Expanded placebo controlled clinical trials examining this application of HA are currently underway.

Adjuvants, Immunologic↗
PubMed2006

Urodynamic effects of intravesical administration of the new small/intermediate conductance calcium activated potassium channel activator NS309 in freely moving, conscious rats.

PURPOSE: We investigated the effects of the new K+ channel activator NS309, which acts on small and intermediate conductance Ca2+ activated K+ channels, on detrusor activity in normal rats. MATERIALS AND METHODS: NS309 was given intravesically at different concentrations to conscious female Sprague-Dawley rats undergoing continuous cystometry. The effects of the drug on oxyhemoglobin induced detrusor overactivity were also tested. RESULTS: Intravesical NS309 (100, 300 and 1,000 ng ml(-1)) increased bladder capacity, micturition volume and intercontraction intervals in a concentration dependent way. NS309 (1,000 ng ml(-1)) given intravesically for 1 hour before instillation of intravesical oxyhemoglobin (250 microM) decreased or completely prevented the detrusor overactivity induced by oxyhemoglobin. CONCLUSIONS: Opening small and intermediate conductance Ca2+ activated K+ channels with NS309 given intravesically increased bladder capacity, micturition volume and intercontraction intervals in a concentration dependent way and prevented oxyhemoglobin induced detrusor overactivity. Results suggest that these channels can be interesting targets for drugs aiming to control micturition.

Administration, Intravesical↗
PubMed2000

Intravesical administration of EGF- dextran conjugates in patients with superficial bladder cancer.

OBJECTIVES: Overexpression of the epidermal growth factor receptor (EGFR) has been reported in bladder cancer and is a potential target for therapy with radionuclides. In this study, we investigated the binding of EGF-dextran-(99m)Tc to the EGFR. The aim of this study was to determine if intravesically administered EGF-dextran conjungate selectively accumulated in the tumor tissue and to correlate the uptake to tumor characteristics. METHODS: Eight patients received the conjugate intravesically for about 30 min followed by bladder irrigation and then transurethral resection. Radioactivity of the biopsy specimens from normal urothelium and tumor areas was measured in a gamma counter. RESULTS: Five patients received EGF-dextran-(99m)Tc, three received dextran-(99m)Tc and one received only (99m)Tc. The 5 patients who received the complete conjugate had a mean ratio of radioactivity between tumor and normal urothelium of 664:1 (range: 2.4-1,710). The dextran-(99m)Tc showed a slightly increased ratio and (99m)Tc did not bind at all. CONCLUSION: The results are encouraging and further studies are warranted to investigate if EGF-dextran could be effective as intravesical therapy, either conjugated with cystostatic drugs or labeled with suitable radionuclides.

Administration, Intravesical↗