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PubMed2003

Microscopic quantification of hypercin fluorescence in an orthotopic rat bladder tumor model after intravesical instillation.

We have previously investigated the possibility of using hypericin as a diagnostic tool for the fluorescence detection of flat bladder carcinoma. In these clinical studies, it was shown that following intravesical application in humans, hypericin becomes selectively localized in transitional papillary carcinoma and carcinoma in situ (CIS). In the present study, we characterized the biodistribution of hypericin in rat bladder tumor and normal bladder layers after intravesical administration. The biodistribution was evaluated using fluorescence microscopy with computerized image analysis to image and quantify the fluorescence of hypericin across the urothelial tumor and normal bladder wall. The results show that the photosensitizer intravesical administration route provides selective labelling of both the tumor and normal urothelium. A hypericin dose and instillation time-dependent increase in the hypericin fluorescence intensity in both the tumor and urothelium was observed, without significant hypericin fluorescence in the submucosa and muscle layers. The highest fluorescence ratios in hypericin accumulation in the tumor and normal urothelium to the muscle layer were achieved at 4 h with 30 micro M hypericin (20:1 for the urothelium to muscle layer and 30:1 for the tumor to muscle layer). The difference in fluorescence intensity in tumor tissue to the muscle layer following instillation of 8 micro M hypericin was 11:1, 25:1 and 28:1 at 1, 2 and 4 h, respectively. The difference in fluorescence intensity in tumor tissue to the muscle layer using 30 micro M hypericin was 17:1, 27:1 and 31:1 at 1, 2 and 4 h, respectively. The highest absolute fluorescence levels were observed in the tumor at 4 h with 30 micro M hypericin instillation. The results suggest that under these conditions, PDT with hypericin is likely to produce uniform urothelial tumor eradication, without causing damage to the underlying muscle layers.

Animals↗

PubMed2004

Multimodal therapy for interstitial cystitis.

Gynecologists have been challenged by the diversity in treatment approaches and the historical absence of effective therapy for interstitial cystisis (IC). Until recently, the only Food and Drug Administration (FDA)-approved treatment was bladder instillation with dimethyl sulfoxide, a moderately effective and safe, albeit invasive, process. The approval in 1996 of pentosan polysulfate sodium (PPS) provided IC patients with an effective and safe oral regimen that specifically targets and repairs the damaged urothelium. Intravesical administration of heparin sulfate or PPS, while not FDA indicated, has also been shown to provide symptom relief. Patients with moderate to severe disease may require a multimodal therapeutic approach utilizing PPS as the foundation. Oral PPS can be combined with antihistamines, analgesics, antispasmodics or antidepressants to provide enhanced pain and symptom relief. Patients with severe disease or flares may benefit from instillation of an anesthetic therapeutic relief solution composed of heparin or PPS combined with sodium bicarbonate and lidocaine. Nonpharmacologic approaches, such as bladder training, biofeedback and dietary changes, can provide supplemental relief. Acute and chronic pain associated with IC can now be effectively managed using a multimodal approach with PPS as the basis.

Administration, Intravesical↗

PubMed2001

Production and characterization of 188Re-C595 antibody for radioimmunotherapy of transitional cell bladder cancer.

UNLABELLED: Bladder cancer was responsible for >12,000 deaths in the United States in 1999. The high-molecular-weight glycoprotein MUC1 mucin is overexpressed on bladder tumors and represents a useful target for radioimmunoscintigraphy and radioimmunotherapy. We report on the production and initial tracer studies of a 188Re-antibody complex directed against this target and intended for intravesical radioimmunotherapy of superficial bladder cancer. METHODS: 188Re perrhenate was eluted from a 188W/188Re generator. C595 antibody was reduced with 2-mercaptoethanol and was labeled in the presence of stannous tartrate. The final reaction mixture contained high-molecular-weight contamination, which was removed from the complex using an affinity separation technique. The specificity and integrity of the antibody complex were tested by radioimmunoassay and size exclusion chromatography. Tumor localization was investigated using an ex vivo model in human cystectomy specimens. Tracer amounts of the complex were also administered intravesically to three patients with bladder cancer, who were then imaged by gamma scintigraphy. RESULTS: The complex was immunoreactive (70% +/- 17%) and specific for MUC1 antigens. A peak corresponding to a protein of 150 kDa was observed on size exclusion chromatography, showing that the complex was homogeneous. Binding to bladder tumors was observed in an ex vivo model in which tumors were successfully imaged in four specimens. The mean tumor-to-normal tissue ratio in ex vivo bladders was 7:1. Tumor uptake after intravesical administration was confirmed in three patients with bladder cancer (mean tumor-to-normal tissue ratio, 4:1). CONCLUSION: The C595 antibody was labeled with 188Re, providing a radioimmunoconjugate with high immunoreactivity and specificity. Its ability to localize in tumors both in an ex vivo model and after intravesical administration to patients has been shown. This approach will now be extended for the therapy of superficial bladder cancer.

Antibodies, Monoclonal↗

PubMed2005

Sustained intravesical interferon protein exposure is achieved using an adenoviral-mediated gene delivery system: a study in rats evaluating dosing regimens.

OBJECTIVES: To evaluate whether a recombinant replication-deficient adenovirus containing the secreted human interferon alpha-2b gene (rAd-IFN) could improve the tissue and urine levels of IFN protein by transducing the urothelium with the secreted human IFN-alpha gene. We also assessed whether varying the interval between rAd-IFN/Syn3 treatments would improve the duration and levels of gene expression. METHODS: The rats received intravesical administration of rAd-IFN at varying concentrations in a formulation containing Syn3, an agent identified that facilitates passage of the adenovirus through the protective barrier of the bladder. Urine was collected daily for 7 days, and human IFN was measured in the urine by enzyme-linked immunosorbent assay. For the redosing studies, the animals received a second dose at varying intervals ranging from 1 to 7 days after the first dose or at longer intervals (30, 60, or 90 days). RESULTS: Rats that received intravesical administration of rAd-IFN in a Syn3 formulation expressed levels of human IFN protein in their urine at peak concentrations of 50,000 to 100,000 pg/mL, but were undetectable by 7 days. Expression was localized to the bladder with only minimal systemic exposure to IFN. Short-term redosing marginally improved the IFN urine concentrations, with maximal levels achieved when a second dose was administered 3 days after a first dose. Although gene expression was attenuated when a second dose was given 5 to 7 days after the first treatment, the levels and duration of IFN expression recovered when the interval was increased to 90 days. CONCLUSIONS: Intravesical treatment with rAd-IFN facilitates high levels of IFN transgene exposure and may be a new approach to treating superficial bladder cancer.

Adenoviridae↗

PubMed2006

A model of hemorrhagic cystitis induced with acrolein in mice.

Acrolein is a urinary metabolite of cyclophosphamide and ifosfamide, which has been reported to be the causative agent of hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of acrolein, however, has not yet been demonstrated. In the present study, the effects of intravesical injection of acrolein and mesna, the classical acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group) received saline or acrolein (25, 75, 225 microg) intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals, mesna was administered intravesically (2 mg) or systemically (80 mg/kg) 1 h before acrolein. Intravesical administration of acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and Evans blue dye exuded, respectively, at doses of 75 microg/bladder), as confirmed by Gray's criteria. Pretreatment with mesna (2-mercaptoethanesulfonic acid), which interacts with acrolein resulting in an inactive compound, inhibited all changes induced by acrolein. Our results are the first demonstration that intravesical administration of acrolein induces hemorrhagic cystitis. This model of acrolein-induced hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.

Acrolein↗

PubMed2003

MK-801 inhibits the micturition reflex in chronic bladder irritation caused by crystalluria in the rat.

Urodynamic and pharmacological studies were performed to investigate the effect of crystalluria on the micturition reflex and the involvement of glutamatergic transmission. The rats, which were given LP-805 (100 mg/kg/day) orally for 12 days, voided crystalluria. The pH of these crystalluria (LP-805 urine) was the same as normal urine. The amount of crystals was 70-100/division magnified 400 x. The end of the crystals was sharp. Intravesical administration of LP-805 urine induced hyperreflexia of the micturition reflex in normal rats. When the infusion solution was changed to LP-805 urine from saline, the latency was reduced to 57.6+/-2.1% of control in single cystometrogram (CMG) or was reduced to 51.4+/-0.9% of control in continuous CMG. The voiding volume was reduced to 52.1+/-3.6% of control in single CMG or was reduced to 62.5+/-0.8% of control in continuous CMG. These parameters were recovered after LP-805 urine was removed. Intravesical administration of acetic acid did not induce hyperreflexia of the micturition reflex in LP-805-treated rats. These data suggest that the chronic irritation by aculeate crystals might induce hyperreflexia of the micturition reflex, which increase afferent neuronal activity. Intravenous administration of MK-801 (0.001 to 1 mg/kg) inhibited the micturition reflex in a dose-dependent manner. The ID50 in LP-805-treated rats (0.03 mg/kg i.v.) was lower than that in normal rats (0.56 mg/kg i.v.). After chronic irritation of the bladder epithelium, MK-801 sensitivity was enhanced for the micturition reflex. These data suggested that crystalluria elicit hyperreflexia in the micturition reflex that mediated with NMDA glutamatergic receptors.

Animals↗

PubMed1992

Murine bladder carcinoma cells present antigen to BCG-specific CD4+ T-cells.

Intravesical administration of Bacillus Calmette-Guérin (BCG) is the most effective therapy for superficial transitional cell carcinoma of the bladder although its mechanism of action is not known. To determine if bladder tumors are capable of antigen presentation and thus might interact directly with BCG-specific T-cells, we studied the murine bladder tumor MB49. MB49 (MHC Class II negative) (IA-), when induced to express IA with interferon, presented BCG to specific CD4+ T-cells obtained from bladder-draining lymph nodes following intravesical BCG administration. This interaction resulted in antigen- and IA-dependent interleukin 2 and tumor necrosis factor production. Interferon also induced MB49 IA expression in vivo. This first demonstration of antigen presentation by epithelial tumors supports new approaches to immunotherapy of these malignancies.

Administration, Intravesical↗

PubMed2006

Effects of goshajinkigan (niu-che-sen-qi-wan) for resiniferatoxin-sensitive afferents on detrusor overactivity induced by acetic acid in conscious rats.

This study was performed to investigate the effects of goshajinkigan, a traditional Chinese herbal mixture, in conscious rats undergoing continuous cystometry. Systemic resiniferatoxin (RTX) pretreatment can block resiniferatoxin-sensitive (C-fiber) nerve-mediated bladder overactivity, such as that induced by intravesical administration of acetic acid. The effects of pretreatment with goshajinkigan and RTX alone or in combination on acetic acid-induced bladder overactivity in conscious rats were also compared. Female SD rats were divided into four groups. Groups 1 and 3 received normal food for 4 weeks, while groups 2 and 4 received goshajinkigan (0.09 g/kg/day) during the same period. Two days after bladder catheterization, groups 3 and 4 received RTX (0.3 mg/kg) injection, while groups 1 and 2 received vehicle alone. Cystometric investigations were performed on all animals 24 hours after RTX or vehicle injection. The effects of intravesical instillation of acetic acid (pH = 4.0) were compared with those of intravesical saline. Goshajinkigan significantly increased threshold pressure, voiding interval, micturition volume, and bladder capacity. Intravesical instillation of acetic acid induced bladder overactivity in both normal rats and in those pretreated with goshajinkigan. However, the effects of acetic acid on voiding interval and micturition volume were significantly different between rats given normal diet and those pretreated with goshajinkigan. The effect of acetic acid was not different between goshajinkigan- and RTX-pretreated rats. The results of the present study indicated that goshajinkigan increases voiding interval, micturition volume, and bladder capacity, and pretreatment with goshajinkigan partially blocks the bladder overactivity induced by intravesical administration of acetic acid in rats.

Acetic Acid↗

PubMed1990

[Absorption of tetrahydropyranyl adriamycin administered intravesically immediately after transurethral resection of bladder carcinoma].

Absorption of tetrahydropyranyl adriamycin (THP) administered immediately after transurethral resection of bladder carcinoma (TUR-Bt) has not been reported. In this study, we have examined the absorption of THP and the systemic toxicity in the early post-TUR period. Of 21 patients with bladder carcinoma, 10 had a solitary tumor and 11 multiple tumors. Twenty mg THP in 40 ml of sterile water was intravesically administered on days 1, 3, 5, 7, 14 and 28, and then every 4th week. The THP solution was retained for 2 hours. The blood THP concentration was measured 30 minutes and 2 hours after the intravesical administration on days 1, 7 and 28. No systemic side effects were observed. Thirteen of the 38 (34%) samples contained a detectable level (more than 1 ng/ml) of THP on the post-TUR-Bt on day 1, 8, of 42 (19%) on day 7, and 3 of 18 (17%) on day 28. Altogether, 24 of the 98 (24%) samples contained more than 1 ng/ml THP. The highest blood THP level was 23 ng/ml on day 1. The differences between frequency of detection of blood THP in the samples at 30 minutes and 2 hours were not statistically significant. The difference between average concentration of blood THP of patients with solitary and multiple tumors also was not significant. These results indicate that intravesical THP administration starting within 24 hours after TUR-Bt can not result in significant systemic absorption of THP, and the systemic toxicity can be avoided.

Absorption↗

PubMed1989

Binding of liposomes to human bladder tumor epithelial cell lines: implications for an intravesical drug delivery system for the treatment of bladder cancer.

Present therapy of human superficial bladder cancer includes the intravesical administration of antitumor drugs and immunomodulators. The purpose of these studies was to determine whether liposomes can bind to human bladder cancer cells and thereby provide a mechanism to improve the delivery of anticancer agents to diseased urothelium. Negatively charged large multilamellar vesicles (MLVs) bound to four different human bladder tumor cell lines (253J, J82, T24, TCCSUP) more avidly than did small sonicated vesicles or vesicles consisting of uncharged phosphatidylcholine (PC). Of the three types of negatively charged MLVs tested, phosphatidylcholine/phosphatidylserine (7:3, mol ratio) (PC/PS) MLVs bound the most. MLV binding to tumor cells was saturable and appeared to be specific. In contrast, the binding of liposomes to normal fetal bladder cells was minimal. These data suggest that targeting of drugs to superficial bladder cancer can be achieved by the intravesical administration of PC/PS MLV.

Drug Carriers↗

PubMed2004

The effect of intravesical sodium nitroprusside on idiopathic detrusor overactivity.

Although nitric oxide (NO) plays an important role in the urethra and outlet region of the bladder, the role of this inhibitory neurotransmitter in the human detrusor remains unclear. We conducted a prospective, randomised, open study on 31 patients with urodynamically proven idiopathic detrusor overactivity in order to examine the effects of intravesical administration of the NO donor sodium nitroprusside (SNP) on detrusor overactivity. Thirty-one consecutive patients (14 male, 17 female; mean age 53.0+/-2.7 years) with idiopathic detrusor overactivity diagnosed by pressure-flow analysis were included in this study. The patients were randomised into two groups. Cystometries were performed with normal saline in the control group ( n=10) and with 7.2 mM SNP solution (2.16 mg/ml) in the study group ( n=21). We urodynamically investigated sensation, maximal cystometric capacity, compliance, instability index, amplitude and frequency of involuntary contractions. No statistically significant differences was found between the first (pressure-flow) and second (saline or SNP cystometry) urodynamic values in the control and study groups (P>0.05). We have demonstrated that SNP does not have any effect on uninhibited bladder contractions. These results suggest that the intravesical administration of SNP is not an effective treatment for detrusor overactivity.

Blood Pressure↗

PubMed1998

[Intravesical instillation of trospium chloride, oxybutynin and verapamil for relaxation of the bladder detrusor muscle. A placebo controlled, randomized clinical test].

Therapy of detrusor hyperactivity with anticholinergic agents often is followed by adverse drug reactions. Intravesical application may be an interesting alternative. A randomised, single-blind, placebo-controlled, mono-centre clinical trial was carried out in 84 patients with urgency or urge incontinence. Due to intravesical administration of oxybutynin (CAS 5633-20-5) (n = 21) and trospium chloride (CAS 10405-02-4) (n = 21), respectively, a significant increase in maximum bladder capacity and decrease of detrusor pressure accompanied by an increase of residual urine were found in comparison to placebo in urodynamical investigations. Improvement of uninhibited bladder contractions occurred leading to higher filling volume. Under verapamil (CAS 152-11-4) (n = 21) no marked changes in the efficacy variables were found compared with placebo. All patients completed the study and were assessed with regard to efficacy and safety. No adverse events or marked changes in the vital signs were reported. The immediate onset of effect and the lack of adverse drug reactions suggest that treatment with topical oxybutynin or trospium chloride is an effective alternative in patients with intolerable side effects when orally treated. In addition, intravesical administration may be indicated in patients with bladder spasms due to indwelling catheter or in order to increase bladder capacity before percutaneous cystostomy.

Adult↗

PubMed1970

Further experiences with intravesical formalin administration in advanced carcinoma of the bladder.

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Formaldehyde↗

PubMed1983

Studies on the permeability of drugs through vesical wall. The fifth report: experiences with intravesical formalin administration.

When some drug is injected into the bladder, it has been found to permeate through the bladder wall, and appear in the serum. Similarly, formaldehyde, which is in some clinical cases injected into the bladder on hemostatic purposes, could produce side effects if a large part of its injected dose is transferred into the serum. We, therefore measured the transfer of the agent into the serum in both experimental animals and human patients. Formaldehyde was found to be transferred into the serum through the bladder of rabbits with cystitis, but only a trace of it appeared in the serum through the normal bladder. The injection of 10 ml of a 10% solution of formaldehyde to rabbits with cystitis was followed by a peak level of 8 gamma/ml in the serum. Judging from this level, the same amount injected to humans would not be high enough to cause any particular problems. In the actual study, the formaldehyde level in the serum of human patients was not detectable by the assay method used.

Animals↗

PubMed2001

Side-effects of oral or intravesical oxybutynin chloride in children with spina bifida.

OBJECTIVE: To evaluate the incidence of side-effects of oral and intravesical oxybutynin chloride in children with meningomyelocele (MMC) and a neurogenic bladder. PATIENTS AND METHODS: The study comprised 225 children with a neurogenic bladder from MMC who were evaluated with urodynamic testing and voiding cysto-urethrography to identify those at high risk of upper tract damage. In all, 101 children (mean age 4.2 years, range 0.25-10) had unco-ordinated detrusor-sphincter function and low compliance; they were treated with either oral or intravesical oxybutynin and clean intermittent catheterization. RESULTS: Of the 101 patients, 67 were treated with oral oxybutynin; in 11 the treatment was discontinued because of the side-effects. The other 34 patients used both clean intermittent catheterization and intravesical oxybutynin. In this group there were side-effects in six patients, including drowsiness, hallucinations and cognitive changes. CONCLUSIONS: Oral and intravesical oxybutynin is effective for managing neurogenic bladder dysfunction, but intravesical administration is safer and better tolerated than oral oxybutynin in the treatment of children with MMC. However, adverse effects such as cognitive impairment can also occur in children treated with intravesical oxybutynin and these patients must be closely monitored because these effects may differ from those with oral administration.

Administration, Intravesical↗

PubMed1997

DMSO: effect on bladder afferent neurons and nitric oxide release.

PURPOSE: Interstitial cystitis (IC), a chronic disorder of the urinary bladder, is characterized by increased voiding frequency, urgency and pain. Patients with IC also exhibit reduced urinary nitric oxide synthase activity. Intravesical administration of dimethyl sulfoxide (DMSO) has been used to provide symptomatic relief in patients with IC. The present experiments were undertaken to determine if intravesical DMSO affects neural pathways involved in bladder function in the rat and if DMSO can influence the release of nitric oxide in the bladder or from afferent neurons. MATERIALS AND METHODS: The effects of intravesical DMSO (10% solution in saline) on reflex bladder activity, firing on bladder nerves and c-fos gene expression in spinal neurons was examined in urethane anesthetized female Wistar rats. The effect of DMSO (1-10%) on nitric oxide release from urinary bladder strips or acutely dissociated dorsal root ganglion cells was monitored in vitro with a porphyrinic microsensor. RESULTS: DMSO acutely increased reflex firing of pelvic nerve efferent axons, decreased bladder capacity and also increased neuronal c-fos expression in spinal cord regions that exhibit c-fos expression after chemical activation of capsaicin-sensitive bladder afferents. DMSO, like capsaicin, also directly released nitric oxide (NO) from both dissociated dorsal root ganglion neurons and from isolated strips of urinary bladder. CONCLUSIONS: These results suggest that DMSO induced stimulation of bladder afferent pathways and NO release from afferent neurons may be a reflection of the initial event in the desensitization of nociceptive pathways in the lower urinary tract (LUT).

Administration, Intravesical↗

PubMed1996

Drug retention following intravesical delivery of fluorouracil therapeutic adhesive in C3H mouse bladder.

We have developed a fibrinogen-based, sustained-retention drug delivery system, therapeutic adhesive (TA), for application to resected tumor beds to reduce local tumor recurrences. In this study we evaluated the feasibility, safety and retention of the TA formulated with 5-fluorouracil (5-FU TA) after intravesical administration in a mouse bladder model. Radiolabeled [14C]5-FU TA or [14C]5-FU solution was delivered intravesically to C3H/He female mice. After drug administration, retention of 14C in the bladder was quantified by storage-phosphor autoradiography. A 2.6-fold increase in retention was observed with 5-FU TA when compared with 5-FU solution. The AUC(2 min-5 h) for 5-FU TA was 685 nmol h/mm2 compared with 260 nmol h/mm3 for 5-FU solution. No signs of toxicity in the bladder tissue or treatment-associated adverse effects were observed in the mice.

Administration, Intravesical↗

PubMed2006

EDTA-induced urothelial cell shedding for the treatment of superficial bladder cancer in the mouse.

AIM: The aim of this study was to determine the effect of intravesical EDTA instillation on the development of intravesically implanted tumor cells in normal mice. METHODS: The mouse bladder tumor (MBT-2) model was used in female C3H/eb mice to evaluate the amount of normal urothelial cell shedding, and the degree of tumor growth inhibition following intravesical EDTA instillation in comparison with phosphate-buffered saline (PBS) instillation. RESULTS: At 1 h after instillation, the number of urothelial cells aspirated was 500-1000 per PBS-treated mouse and 10,000-20,000 per EDTA-treated mouse (P < 0.00001). The bladder weight, which reflected the effect of the agent on the tumor, was similar in the untreated and PBS-treated mice (105.46 +/- 46 mg and 106.2 +/- 50 mg, respectively). It was significantly lower in the EDTA-treated mice (80.4 +/- 42 mg) (P = 0.0045). CONCLUSIONS: Intravesical administration of EDTA results in significant normal and neoplastic urothelial cell shedding. Intravesical irrigation with EDTA may prevent adherence of the malignant cells to the bladder wall following tumor resection.

Administration, Intravesical↗