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An open pharmacokinetic study of hexylaminolevulinate-induced photodiagnosis after intravesical administration.

BACKGROUND AND OBJECTIVES: Hexylaminolevulinate-mediated photodiagnosis of superficial bladder cancer recently gained marketing authorisation in Europe and is therefore being used increasingly, especially to visualise flat tumours such as carcinoma in situ. Although no significant adverse effects related to the drug have been reported to date, precise information with respect to the safety of this procedure in clinical practice has not yet been published. In the present study, we investigated the possible systemic absorption of different hexylaminolevulinate concentrations and characterised the adverse effects after bladder instillation. METHODS: Twelve patients with known bladder cancer received a 2-hour administration of 50 mL of phosphate-buffered saline containing 4 mmol/L, 8 mmol/L or 16 mmol/L of hexylaminolevulinate. Safety was primarily evaluated by monitoring adverse effects. Standard haematology and clinical biochemistry were assessed by the local hospital laboratory. Measurements of hexylaminolevulinate, 5-aminolevulinate and protoporphyrin IX in plasma and solution collected after instillation were performed, as were fluorescence measurements in the urothelium and the skin by using an optical fibre-based spectrofluorometer. RESULTS: No hexylaminolevulinate was found in the plasma. Furthermore, 5-aminolevulinate and protoporphyrin IX showed no significant increases in plasma after intravesical instillation of hexylaminolevulinate 4 mmol/L, 8 mmol/L or 16 mmol/L for 2 hours. This implies a very low systemic absorption at the administered doses with a hexylaminolevulinate uptake from the bladder of about 5%. Neither skin sensitivity nor adverse reactions that could be attributed to the drug were reported. Renal and liver function were not affected by the hexylaminolevulinate doses used in this study. CONCLUSION: We demonstrated for the first time that hexylaminolevulinate-mediated photodiagnosis is a safe procedure for a patient undergoing this examination, the drug being only minimally systemically absorbed after intravesical instillation. Therefore, no or only minimal adverse effects compared with those seen with conventional photosensitising agents can be expected.

Administration, Intravesical↗

Intravesical administration of gemcitabine in superficial bladder cancer: a phase I study with pharmacodynamic evaluation.

OBJECTIVE: To determine, in a phase I trial, the local and systemic toxicity and pharmacodynamics of intravesical gemcitabine in patients with superficial bladder cancer. PATIENTS AND METHODS: Twelve patients with histologically confirmed carcinoma localized to the bladder wall (stage T1 or Ta) resistant to previous administration of anticancer drugs and/or of bacille Calmette-Guérin were enrolled. They initially received intravesical gemcitabine starting at 500 mg and increased in 500 mg increments to 2000 mg. Three patients were treated at each dose level. RESULTS: There was no evidence of systemic toxicity and local toxicity was minimal. A pharmacological evaluation showed that gemcitabine was undetectable in plasma and its inactive metabolite (2',2'-difluorodeoxyuridine) was present at a mean (SD) concentration of 1.39 (1.05) mumol/L Deoxycytidine kinase was present in tumour tissue samples, and its activity was 27.3 (12.6) pmol/h/mg tissue; deoxycytidine deaminase activity varied from undetectable to 616 pmol/h/mg tissue. CONCLUSION: Intravesical gemcitabine appears to be well tolerated with no systemic and minimal local toxicity even at the highest dose (2000 mg). A phase II trial of intravesical gemcitabine at 2000 mg given weekly for six consecutive weeks is now in progress in patients with superficial bladder cancer.

Administration, Intravesical↗

Systemic, bladder wall, and bladder tumor concentration of misonidazole following intravesical administration in the rat.

The hypoxic-cell radiosensitizer misonidazole was administered intravesically to normal and to bladder tumor-bearing female Fischer rats. Drug concentration was measured in the bladder wall, the tumor and in the serum using high pressure liquid chromatography at different times following administration. The data shows that misonidazole is readily adsorbed by the bladder wall and the tumor with tissue levels reaching up to 10 times those measured in the serum.

Animals↗

Whole bladder photodynamic therapy for orthotopic superficial bladder cancer in rats: a study of intravenous and intravesical administration of photosensitizers.

PURPOSE: Photodynamic therapy after intravenous injection of Photofrin (QLT Phototherapeutics, Vancouver, British Columbia, Canada) results in a contracted bladder and skin photosensitivity, which limits its clinical application. In an attempt to overcome these limitations photodynamic therapy after intravesical instillation of Photofrin or 5-aminolevulinic acid (ALA) in an orthotopic rat bladder tumor model was explored and compared with intravenous Photofrin for photodynamic therapy efficacy and phototoxicity. MATERIALS AND METHODS: At 2 weeks after bladder implantation of 1.5 x 10(6) AY-27 tumor cells animals were randomly grouped. Photofrin was administered (5 mg./kg. intravenously and 2 mg./ml. intravesically). The ALA concentration for intravesical instillation was 300 mM. Whole bladder photodynamic therapy with graded doses of light (lambda = 630 nm.) was performed 4 hours after drug administration. Tumor control and complications were evaluated. RESULTS: Photodynamic therapy with intravenous Photofrin plus 100 J./cm.(2) light resulted in severe bladder damage. Of 10 rats 6 died and 2 of the 10 that received 50 J./cm.(2) died. There were no photodynamic therapy related deaths in groups receiving intravesical instillation of Photofrin or ALA that also received 50 to 100 J./cm.(2) Median survival in rats treated with ALA intravesically plus 75 J./cm.(2) (77 days), Photofrin intravesically plus 50 (67) or 100 J./cm.(2) (76) and Photofrin intravenously plus 50 J./cm.(2) (60) were significantly different from that in controls (44). CONCLUSIONS: Intravesical instillation of Photofrin or ALA can achieve the same photodynamic therapy efficacy as intravenous Photofrin in this orthotopic rat bladder tumor model with less phototoxicity to normal tissues.

Administration, Intravesical↗

[Massive secondary psoriasiform dermatitis secondary to intravesical administration of mitomycin C].

We report on a patient who had been submitted to vesical diverticulectomy. Pathological examination of the surgical specimen revealed G2T1 urothelial carcinoma. Intravesical chemotherapy with mitomycin C was instituted. Following the sixth instillation, the patient developed widespread psoriasiform dermatitis and required admission to hospital. Remission was achieved with drug withdrawal and symptomatic treatment. The literature is reviewed.

Aged↗

Intravesical administration of bacillus Calmette-Guérin in patients with recurrent superficial carcinoma of the urinary bladder: report of a prospective, randomized trial.

In an attempt to prevent, delay, or reduce further tumor occurrence, 88 patients with recurrent, superficial carcinoma of the urinary bladder were randomly assigned to receive either standard therapy (cystoscopy with fulguration) or standard therapy and bacillus Calmette-Guérin (BCG). BCG was administered intravesically and percutaneously once weekly for 6 weeks. No serious toxicity was seen. There were 43 evaluable patients in each of the two groups. Results in the BCG group versus the control group were as follows: reduction in the number of recurrent tumors (43 vs 27 patients [P less than 0.001] ); conversion to negative cytology (11 of 33 vs three of 34 patients [P less than 0.05] ); and tumor progression requiring cystectomy (three vs 15 patients [P less than 0.001] ). Disease-free interval (P less than 0.001), time with negative cytology (P less than 0.001), and time to progression of disease (P less than 0.003) were longer in patients treated with BCG. These results indicate that the combination of standard therapy and BCG is more effective than standard therapy alone in patients with recurrent superficial bladder tumors.

Adult↗

Immunostimulatory CpG oligonucleotides reduce tumor burden after intravesical administration in an orthotopic murine bladder cancer model.

Bacillus Calmette-Guérin is established in the prophylaxis of recurrent intermediate and high-risk superficial bladder cancer and induces an unspecific, Th1-biased local immune response. Small CpG oligonucleotides (CpG ODN) containing a central unmethylated CpG motif are able to mimic the immunostimulatory activity of bacterial DNA. The purpose of the present study was to evaluate the antineoplastic properties of intravesically administered CpG ODN in an orthotopic murine bladder cancer model. MB49 tumor cell suspension was instilled transurethrally in female C57/BL6 mice on day 0. Mice were divided in three groups of 12 animals. Four mice in each group received either stimulative CpG ODN, non-stimulative GpC ODN or PBS intravesically: group I on day 3, group II on day 5, group III on day 7. After sacrifice 7 days after treatment, bladders were removed and histological examinations were performed. Single instillation of CpG ODN revealed antineoplastic effects in every group demonstrated by significantly lower bladder weight compared with non-stimulative GpC ODN- and PBS-treated mice. Histological examination showed extensive infiltration of macrophages and lymphocytes in CpG ODN-treated mice, whereas PBS- and GpC ODN-treated mice showed solid tumor growth with only few leucocytes. Intravesically applied immunostimulative DNA demonstrated antitumoral activity in an orthotopic murine bladder cancer model. A single instillation seems to be sufficient to reduce tumor load.

Animals↗

Intravesical recombinant tissue plasminogen activator for the prevention of implantation-mediated bladder tumor recurrence.

The mechanism by which intravesical recombinant tissue plasminogen activator (rTPA) prevents tumor cell adherence to injured bladder surfaces, and the optimal parameters for the in vivo use of rTPA for adherence prevention, were evaluated. Intravesical rTPA decreased tumor cell adherence to sites of urothelial injury as a direct function of drug concentration in the intravesical fluid. Recombinant TPA concentrations of 1 mg/ml and 0.1 mg/ml significantly decreased tumor cell adherence relative to the control group. The efficacy of rTPA in removing adherent cells was time-dependent with maximal activity occurring at 15 min or later following intravesical administration. Intravesical rTPA effectively reduced the size of the tumor inoculum when administered either concomitant with, or subsequent to, tumor cell exposure. The relative efficacy of these two approaches was dependent upon the presence of serum in the intravesical fluid. Administration of rTPA concomitant with tumor cell exposure proved more effective in the absence of serum, while postadherence administration was more effective in the presence of 10% fetal calf serum. The addition of exogenous plasminogen to the rTPA solution did not increase anti-adherence activity relative to rTPA alone. However, blockade of endogenous plasminogen conversion with systemically administered epsilon-amino-caproic acid reversed the anti-adherence activity of exogenous rTPA. In vitro experiments evaluating cellular adherence to fibrin substrate confirmed that rTPA's anti-adherence activity was dependent on the presence of plasminogen. Exogenous rTPA administered immediately following tumor cell adherence decreased tumor cell implantation in animals receiving low to moderate tumor inoculums. These data suggest that rTPA prevents cellular adherence as a result of plasminogen activation and subsequent fibrinolysis. Intravesical rTPA administered in sufficient concentration for relatively short periods of time effectively reduces the adherent tumor inoculum and alters implantation as an inverse function of the tumor inoculum. This approach represents a novel strategy which may prove applicable for the prevention of implantation-mediated tumor recurrence at sites of surgical trauma.

Administration, Intravesical↗

Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: a comparative Phase II study.

OBJECTIVES: To evaluate the efficacy of electromotive administration (EMDA) of intravesical mitomycin-C (MMC) in patients with superficial bladder tumors and to evaluate the toxicity of the treatment. METHODS: Thirteen patients with multifocal Stages Ta-T1 and G1-G2 transitional cell carcinoma (TCC) of the bladder, primary or recurrent (group A), received MMC 40 mg (retained in the bladder for 2 hours) once a week for 8 weeks. Fifteen patients with the same characteristics (group B) were treated with EMDA/MMC at a current of 15 mA for 20 minutes once a week for 8 weeks. All lesions in the bladder except one (marker) were resected in each patient. RESULTS: In group A, 5 of 12 patients (41.6%) demonstrated complete macroscopic and histologic disappearance of the marker lesion (complete response [CR]). In group B, 6 of 15 patients (40%) had a similar CR. Recurrence rate in responders was 60% in group A versus 33% in group B after 7.6 and 6 months, respectively. Disease-free interval was 14.5 months in the EMDA/MMC group compared to 10.5 months in the MMC group. Side effects were few. CONCLUSIONS: In intermediate risk patients with TCC of the bladder, EMDA/MMC was not superior to MMC alone with a CR rate of 41% versus 41.6%. In responders, a lower recurrence rate and a longer disease-free interval were observed in the EMDA/MMC group.

Administration, Intravesical↗

Intravesical BCG administration in the guinea pig. II. Immunohistochemical characterization of cellular infiltrate after one or two cycles of intravesical BCG.

The intravesical administration of bacillus Calmette-Guérin (BCG) is used as an adjuvant therapy after transurethral resection for superficial bladder cancer in man. The aim of this study was to characterize with monoclonal antibodies the cellular infiltrates in the bladder wall occurring after one or two cycles, each comprising six weekly intravesical BCG administrations in guinea pigs. BCG-RIVM and BCG-TICE were instilled once a week in undamaged bladders at weeks 1-6 and 11-16, respectively, and retained in the bladder for 1 h. Autopsy was performed 1 week after the last BCG administration at weeks 7 and 17. By routine histology, a single BCG course induced scattered focal infiltrates consisting of minor to severe accumulations of mononuclear cells. After two cycles of BCG, a much more severe inflammatory reaction sometimes occupying almost the total bladder mucosa was noted. The major component of this inflammation was mononuclear cells, mainly lymphocytes, while typical BCG granulomas were occasionally observed. In general, the epithelial layer of the bladder showed no visible alterations. Immunohistochemical staining showed that the majority of mononuclear cells present in the infiltrate were T-cells. Widely scattered B-cells and macrophages were also present, but were much fewer in number than the T-cells. In general, T-helper/inducer cells were more frequent than T-suppressor/cytotoxic cells. Pseudofollicles, also noted after H&E staining, consisted mainly of B-cells. The second series of BCG administrations produced pseudofollicles in the infiltrates in all animals investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Intravesical liposome administration--a novel treatment for hyperactive bladder in the rat.

OBJECTIVES: To examine the effect of intravesical administration of liposomes (LPs) on chemically induced bladder hyperactivity in the rat. It has been suggested that interstitial cystitis (IC) is associated with a dysfunctional or leaky epithelium. Thus, enhancement of epithelial barrier function might be useful in the treatment of IC. LPs are vesicles that are concentric phospholipid bilayers separated by an aqueous compartment and can fuse with cells to provide a molecular film that can promote wound healing. METHODS: The intravesical pressure was recorded using a transurethral catheter in adult female Sprague-Dawley rats anesthetized with urethane (1.2 g/kg subcutaneously). Some animals were pretreated with capsaicin (125 mg/kg subcutaneously) 4 days before the experiments. Continuous cystometrograms were performed by slowly filling the bladder (0.04 mL/min) with solutions of varying compositions, including saline, acetic acid (AA, 0.1%), potassium chloride (KCl, 500 mM), protamine sulfate (PS, 10 mg/mL), LPs, PS/KCl, or LPs/KCl. The parameters measured included the intercontraction interval (ICI), amplitude of bladder contractions, compliance, and micturition pressure threshold. RESULTS: The ICI was decreased after exposure to AA (79.8% decrease) or PS/KCl (81% decrease); however, the ICI was not changed after LPs, PS, or KCl alone. The decreased ICI was partially reversed after infusion of LPs (172.8% increase) or LPs/KCl (63% increase), but was not significantly changed after switching to saline or KCl administration. Pretreatment with capsaicin delayed the onset of the irritative effects of AA by approximately 30 to 60 minutes, but had not changed the magnitude after 2 hours of infusion. CONCLUSIONS: Intravesical administration of PS/KCl or AA activates capsaicin-sensitive and capsaicin-resistant afferents in a time-dependent sequence that is partially reversed by LP infusion. We hypothesize that LPs might enhance the barrier properties of a dysfunctional uroepithelium and increase resistance to irritant penetration. Thus, intravesical LP administration could be a novel treatment of patients with IC.

Administration, Intravesical↗