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PubMed1994

Intravesical instillation chemotherapy of adriamycin with or without verapamil for the treatment of superficial bladder cancer: the final results of a collaborative randomized trial.

A collaborative randomized clinical trial on the intravesical administration of Adriamycin (ADM) with or without verapamil (VR), a calcium-channel blocker, as chemotherapy of superficial bladder cancer (Ta, T1) was carried out at two universities, Okayama and Kagoshima, and their affiliated hospitals. Arm A consisted of ADM given at 50 mg/50 ml saline, and arm B consisted of ADM given at 50 mg/40 ml saline plus five ampules (25 mg/10 ml saline) of injectable VR. The drugs were instilled into the bladder for 3 consecutive days, and three such courses were given with a 4-day interval between each course for a total of nine instillations. A total of 96 patients (48 in arm A and 48 in arm B) were entered into this study. The two treatment groups showed no significant difference in background factors. Of the 40 evaluated arm-A patients, 24 (60.0%) showed a response (CR + PR), whereas 19 (48.7%) of the 39 patients in arm B responded. The difference between these response rates was not statistically significant. As for adverse reactions to the intravesical chemotherapy, local inflammatory symptoms were observed in half of the patients, although no systemic reaction was observed. No significant difference was found between arm A and arm B, except for urinary turbidity. In conclusion, at the dose employed in the present clinical trial, there was no clear enhancement of the effect of ADM combined with VR in patients with superficial bladder cancer. Further clinical studies are required to determine the optimal doses of ADM and VR for their combination in intravesical chemotherapy.

Administration, Intravesical↗

PubMed1996

Vesico-hepato-renal cycling of acidic drugs via their reactive acyl glucuronide metabolites? Studies with diflunisal in rats.

1. Deconjugation-reconjugation cycling of acidic drugs is known to occur in vivo via the hydrolysis of their reactive acyl glucuronide metabolites during their circulation in the blood (systemic cycling) or during their passage through the gut after biliary excretion (enterohepatic cycling). Whether such cycling occurs after renal excretion via hydrolysis in the urinary bladder followed by absorption of liberated drug (vesico-hepato-renal cycling) was investigated in rats using diflunisal (DF) and its acyl glucuronide (DFAG) as model compounds. 2. After administration of DF (1 mg/0.5 mL buffer, pH 7) into the bladder of anaesthetized bile-exteriorized rats, DF appeared rapidly in plasma, achieving peak concentrations of 7 micrograms/mL at 1 h. At 4 h, 30% of the dose was recovered as metabolites, mainly DFAG and DF phenolic glucuronide (DFPG) in bile, while 30% was recovered as unchanged DF from the bladder. 3. By contrast, after intravesical administration of an equimolar amount of DFAG at pH 7 or 5, DFAG itself was not detectable in plasma. Plasma concentrations of DF were barely detectable, with only approximately 1% of the administered dose recovered as metabolites in bile. 4. The data thus show that, although DF itself undergoes facile absorption from the urinary bladder of healthy rats, vesico-hepato-renal cycling of DF via DFAG appears to be of only minor quantitative importance.

Administration, Intravesical↗

PubMed1993

Effect of different local and systemic therapy upon urinary bladder cytology.

1,900 cytological analyses of urine and bladder washings were made in 127 patients with urothelial bladder carcinomas before, during and after therapy. Following transurethral resection, all patients were treated by intravesical instillation of mitomycin C or thiotepa. Because of a locally advanced bladder carcinoma, 26 patients who were not candidates for radical cystectomy were given an integrated treatment of radiotherapy and chemotherapy. Intravesical administration of mitomycin C and thiotepa as well as integrated radiotherapy and chemotherapy induce a variety of cytological effects (toxic and/or metabolical) which may lead to cytological misinterpretations in the follow-up. DNA measurements by means of single-cell spectrocytophotometry show that the cytological effects induced by the above-mentioned therapies are not accompanied by an increase in the nuclear DNA content. It is concluded that the knowledge of these induced effects is mandatory for a correct interpretation of urinary cytology in the follow-up. Considering these effects and the clinical history, bladder carcinoma recurrences during and after intravesical chemotherapy or integrated radiotherapy and chemotherapy may be detected early by urinary cytology in the hands of an experienced cytopathologist or urologist. Furthermore, alterations of the urinary cytology occur after systemic application of cyclophosphamide and under immunosuppressive therapy.

Administration, Intravesical↗

PubMed1991

Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients.

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Intravesical↗

PubMed1991

The detection of phthalocyanine fluorescence in normal rat bladder wall using sensitive digital imaging microscopy.

The ability to detect photosensitisers in tissue at a microscopical level is important when studying photodynamic therapy (PDT) in both normal and malignant tissue. We have studied the fluorescence distribution of aluminium sulphonated phthalocyanine (A1SPc) in the normal rat bladder using a cooled CCD (charge coupled device) imaging system with computerised image processing. This system makes it possible to carry out a quantitative assessment of photosensitiser fluorescence in the various layers of the bladder wall. The highest fluorescence intensities were obtained within 1 h of intravenous administration but there was little selectivity of uptake between layers. A1SPc was eliminated from the deeper muscle layers more quickly than from the superficial layers of the bladder wall so that by 24 h a 4:1 ratio of fluorescence intensity was apparent which persisted at least until 72 h, although the absolute amount of photosensitiser declined. Following irradiation by red light (675 nm), photobleaching of the sensitiser in the deeper layers further increased this ratio. Direct absorption of A1SPc by the bladder wall following intravesical administration proved unreliable.

Administration, Intravesical↗

PubMed1987

Intravesical chemotherapy.

A total of 85 cases treated by intravesical administration of adriamycin (ADM) at Okayama University and other cooperating institutions were examined. Instillation of 50 mg adriamycin dissolved in 30 ml physiological saline was performed in two courses of 3 consecutive days, with a 4-day interval between the courses. The response rate was 70.6%. Following instillation therapy transurethral resection (TUR) was carried out in 69 cases (80%), segmental cystectomy in 7, and total cystectomy in 3. The follow-up period averaged 42 months, during which the recurrence rate was 57%; recurrence occurred within 18 months in 80% of these cases. Since the recurrence per patient-month x 100 was 3.348, the precise effect of intravesical chemotherapy in the prevention of recurrence was unclear. There were 9 cases of advanced disease (11% of the total, 18% of cases with recurrence). One patient with CIS (flat invasive tumor) seemingly achieved CR, but died 43 months after treatment due to metastatic disease. While this method is not always indicated in cases of CIS (flat invasive tumor), in cases in which it is indicated a drug causing only limited stimulation of the bladder mucosa should be used and long-term follow-up is essential.

Administration, Intravesical↗

PubMed1989

In vitro intravesical instillation of anticholinergic, antispasmodic and calcium blocking agents (rabbit whole bladder model).

The systemic side effects accompanying oral pharmacotherapy of neurogenic bladder dysfunction present significant drawbacks to this type of therapy. In these studies we investigated the effect of intravesical administration of anticholinergic, antispasmodic and calcium blocking agents on pressure response mediated by field stimulation and bethanechol. We used the rabbit in vitro whole bladder model for these experiments. The bladder from a mature male NZW rabbit was mounted in an organ bath as a whole bladder preparation. After control field stimulation and bethanechol stimulation, 20 ml. of saline containing the specific drug being evaluated was instilled into the bladder. At 30 minute intervals, the responses to field stimulation and bethanechol were determined. Two hours after instillation of 100 microM of each specific drug, the inhibition of the contractile response to bethanechol and field stimulation (as % inhibition) was as follows: oxybutynin (95%/64%), verapamil (85%/81%), atropine (68%/31%), diltiazem (47%/39%), and imipramine (44%/47%). Atropine and oxybutynin suppressed the contractile response of the bladder to bethanechol to a much greater extent than that to field stimulation, while verapamil, diltiazem and imipramine suppressed the contractile response to bethanechol and field stimulation to approximately the same extent. Two hours after drug instillation, the intravesical solution was washed out and replaced with saline, but the recovery of the bladder contraction was slow and incomplete. The results of this study suggest that the use of self-intravesical instillation to suppress bladder contractility should be a good therapeutic approach for patients with neurogenic bladder, especially those who are already managed by intermittent catheterization.

Administration, Intravesical↗

PubMed1999

Intravesical capsaicin in patients with detrusor hyper-reflexia--a placebo-controlled cross-over study.

The aim of this study was to determine whether intravesical treatment with capsaicin could block detrusor hyper-reflexia (DH) and alter the substance P content, nerve fibres and mucosa of the bladder. Twelve patients with spinal cord disease with DH and urinary incontinence resistant to anticholinergic treatment underwent intravesical administration of 50 ml 2% lignocaine. followed by either 100 ml 1 mmol/l capsaicin or 100 ml physiological saline for 30 min. Cross-over to the alternative treatment took place after 4 weeks. Varying degrees of burning sensation were experienced by all but one patient during the capsaicin treatment and precluded the possibility of conducting studies of this type in a blind manner. No preference for capsaicin treatment was found, and micturition and VAS scores were unchanged after treatment with capsaicin. The mean volume of the contents of the bladder at which DH first appeared was 175 ml after saline and 195 ml after capsaicin (mean difference 20 ml with a 5% confidence interval from -25 to 65). Bladder biopsies taken 2 weeks after treatment with capsaicin showed more pronounced inflammation, superficial haemorrhage, squamous epithelial metaplasia and a more condensed bladder stroma. Immunohistochemical staining for substance P and neuronal cell adhesive molecule revealed the presence of small terminal axons and small nerve bundles in all of the biopsies. Intravesical treatment with capsaicin did not have a beneficial effect on DH or a destructive effect on nerve fibres. It did, however, produce significant reactive changes in the mucosa of the bladder.

Administration, Intravesical↗

PubMed1992

Soman levels in kidney and urine following administration to rat, guinea pig, and marmoset.

Concentrations of C(+/-)P(+/-)-soman (1,2,2-trimethylpropyl methylphosphonofluoridate) in urine of anaesthetized, atropinized and artificially ventilated rats, guinea pigs and marmosets were determined 1-4 h after iv administration of 1-6 LD50 of the agent and in the kidneys 1 h after iv administration of 2-6 LD50 14C-C(+/-)P(+/-)-soman. The concentrations of the toxic C(+/-)P(-)-isomers in both urine and kidneys of the rat were at least two orders of magnitude higher than the corresponding levels in the two other species. Relatively high urine concentrations were also found for C(+/-)P(+/-)-soman-intoxicated (6 LD50) rats pretreated with the nontoxic soman analogue PDP (1,2,2-trimethyl dimethylphosphinate), which considerably decreases the persistence of C(+/-)P(-)-soman in rats, or the carboxylesterase inhibitor CBDP [2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide]. The lethal effect brought about by intravesical administration of C(+/-)P(+/-)-soman in rats showed that the agent can easily be reabsorbed from the bladder. It is concluded, that this reabsorption does probably not explain the previously observed persistence and "late toxicity" of C(+/-)P(+/-)-soman in rats, although the amount of renally excreted C(+/-)P(-)-soman (ca. 1% of the administered dose) should be sufficient for a toxicologically significant effect.

Administration, Intravesical↗

PubMed2001

Systemic effects of intravesical atropine sulphate.

OBJECTIVE: To investigate systemic antimuscarinic activity after the intravesical administration of 6 mg of atropine sulphate. SUBJECTS AND METHODS: Ten subjects were recruited to an open study in accordance with strict inclusion and exclusion criteria. Each subject received an instillation of 6 mg atropine sulphate diluted to 20 mL with normal saline. All variables were measured at baseline (before instillation) and the instilled solution retained for at least 2 h. After instillation systemic antimuscarinic activity was monitored every 20 min for 2 h then hourly for the next 4 h. The measurements included blood pressure, sublingual temperature, pulse rate, peak expiratory flow rate, lacrimation and salivation rates; all variables were analysed statistically. Facial skin was also observed for hyperaemia. All subjects were questioned about any known symptoms produced by antimuscarinic agents. The heart rate was recorded continuously before and after instillation using a Holter monitor. RESULTS: None of the variables changed significantly after instillation and the Holter analysis showed no relevant variation in heart rate. All subjects consistently denied any antimuscarinic symptoms. One subject had mild cutaneous hyperaemia, as reportedly occurred consistently when her bladder was distended (> 500 mL). Immediate catheterization drained 600 mL and the hyperaemia resolved. CONCLUSION: The failure to detect systemic antimuscarinic activity at a dose which has previously been shown to suppress detrusor activity suggests that intravesical atropine therapy is safe for further study by clinical trial, and might provide a treatment for detrusor hyper-reflexia that is free from side-effects.

Administration, Intravesical↗

PubMed1998

Intravesical electromotive drug administration technique: preliminary results and side effects.

PURPOSE: We performed intravesical electromotive drug administration (EMDA) for various bladder disorders during a 3-year period and assessed the technique, possible applications, complications and outcomes of this procedure. MATERIALS AND METHODS: Intravesical EMDA was performed with local anesthetics for transurethral surgery and in combination with dexamethasone for the treatment of noninfectious chronic cystitis (interstitial/radiation cystitis), with mitomycin C for recurrence prophylaxis of high risk superficial bladder cancer and with oxybutynin/bethanechol for the hyperreflexive/acontractile detrusor. A standardized power source and electrode catheter were used for 215 treatments in 84 patients. RESULTS: Transurethral bladder tumor resections were pain-free in 10 of 12 patients. Of the 25 patients with chronic noninfectious cystitis 15 were free of symptoms for a mean of 6.6 months, and there was a 73% increase in mean bladder capacity from 244 before to 421 cc after EMDA. Of the 16 patients with superficial bladder cancer 9 were free of recurrence for a mean of 14.1 months. In 10 of 14 patients with acontractile detrusors urodynamic examination showed detrusor contraction during EMDA of bethanechol. There were no contractions without electric current. EMDA of oxybutynin reduced detrusor hyperreflexia. A bladder ulcer was the single severe local complication and 4.6% of patients, mainly those with chronic cystitis, reported significant post-EMDA bladder/urethral pain. Minor side effects accounted for 23% of all treatments. No systemic side effects occurred. CONCLUSIONS: Intravesical EMDA is effective and innocuous. The therapeutic concept combines the advantages of increased drug administration without systemic side effects.

Administration, Intravesical↗

PubMed1996

Nerve fibres in urothelium and submucosa of neuropathic urinary bladder: an immunohistochemical study with S-100 and neurofilament.

Intravesical administration of drugs has been used commonly in spinal cord injury patients to suppress detrusor hyperreflexia (eg oxybutynin, verapamil, terodiline) or, to initiate a micturition reflex (eg 15S 15-methyl prostaglandin F2 alpha, protaglandin E2); however, the response has been variable and sometimes, unpredictable. This prompted us to study the presence of nerve fibres in the vesical urothelium and submucosa in mucosal biopsies taken from the dome and trigone (obtained prior to performing a therapeutic procedure eg, vesical lithotripsy, or a diagnostic cystoscopy) in 47 consecutive, unselected paraplegic/tetraplegic patients with a neuropathic urinary bladder. Nerve fibres were demonstrated by routine immunohistochemical technique using commercially available monoclonal and polyvalent antibodies against S-100 (DAKO A/S, Glostrup, Denmark) and Neurofilament (MILAB, Malmo, Sweden). Biopsy specimens were graded for the presence of nerve fibres on a 0-3 scale for urothelium, and superficial/deep submucosa separately in a blind and randomised manner. Virtually no fibre presence was found in one paraplegic patient and no superficial or single fibres were noted in a tetraplegic patient. Absence of C-fibre hyperplasia (Grade 0) was found in nine cases (paraplegic: 4; tetraplegic: 5); Grade 1 hyperplasia was observed in 17 cases (paraplegic: 4; tetraplegic: 13); Grade 2 hyperplasia was seen in 11 cases (paraplegic: 7; tetraplegic 4); and Grade 3 hyperplasia was noticed in eight cases (paraplegic 3: tetraplegic: 5). The magnitude of C-fibre hyperplasia was not significantly different between paraplegic and tetraplegic patients (chi(2) = 4.64; P = 0.3262). The relationship, if any, between the degree of C-fibre hyperplasia and duration of paralysis was studied by categorising patients as < 5 years, and > 5 years of paralysis. No evidence of single fibre or fibre bundle hyperplasia (Grade 0) was seen in five and six cases, grade 1 hyperplasia in six and 11 cases, grade 2 hyperplasia in two and nine cases, and grade 3 hyperplasia in three and five cases respectively in these two categories of patients. (chi(2) = 1.92; P = 0.58). The possible relationship between C-fibre hyperplasia in the vesical mucosa/submucosa and (i) the vesical response to intravesical drug administration; (ii) the vesical urothelial proliferation arrest; (iii) the electrical stimulation of urinary bladder by implanted electrodes (sacral anterior root stimulator); and (iv) long-term indwelling urethral Foley catheter drainage, are discussed with illustrative case reports. In conclusion, mucosal biopsy and study of nerve fibres in urothelium and submucosa of neuropathic bladder has helped to generate hypotheses on the association between C-fibre hyperplasia and response to intravesical pharmacotherapy and the predictive value of such a study in identifying those patients who are likely to respond to intravesical pharmacotherapy.

Adult↗

PubMed1991

Oral or intravesical bacillus Calmette-Guerin immunoprophylaxis in bladder carcinoma.

A total of 71 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumor. All patients had stage pTa or pT1 transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The patients were assigned to 3 treatment groups: control group--transurethral resection discontinued within the study, oral bacillus Calmette-Guerin (BCG) group--transurethral resection of bladder tumor plus BCG (Moreau) and intravesical BCG group--transurethral resection of bladder tumor plus BCG. Of 9 patients in the control group 8 (89%) experienced tumor recurrence during a mean followup of 20 months. Of the 28 patients in the oral BCG group 11 (39.3%) had recurrence during a mean followup of 36 months. Of the 34 patients in the intravesical group 6 (18%) had recurrence in a 24-month mean followup. The incidence of complications was higher in the intravesical (41.2%) than in the oral BCG group (28.5%). These results show that intravesical BCG is a more effective immunotherapy; however, oral BCG can be used in patients who do not accept intravesical BCG administration.

Administration, Intravesical↗

PubMed2002

[Therapeutic effects of intrarectal administration of oxybutynin].

OBJECTIVES: Oxybutynin is a drug of choice in the treatment of the detrusor instability. However the therapeutic doses given orally produce very often side effects due to oxybutynin anticholinergic properties (atropine-like action). The responsible compound is mainly the active oxybutynin metabolite-N-desethyl-oxybutynin, which is the result of the oxybutynin metabolism in liver (so-called first pass metabolism). Therefore it seems, that an attempt of the drug administration via the intrarectal route is an interesting alternative, which maintains the high oxybutynin concentration with the simultaneous reduction of the N-desethyl-oxybutynin. PATIENTS AND METHODS: We qualified 20 patients for our study (12 men and 8 women, mean age 45.6) with the urodynamically proven detrusor instability. Patients with a neurogenic origin of detrusor instability were excluded from the study. Patients treated with oral oxybutynin in a dose of 5 mg b.i.d. and with strongly pronounced atropine-like side effects, making impossible the continuation of the therapy were offered an intrarectal form of oxybutynin in a dose of 5 mg b.i.d. Treatment efficiency was evaluated on the base of the patients symptoms (side effects, urgency, incontinence, frequency). RESULTS: 15 patients (75%) had pronounced side effects, leading to the oral treatment discontinuation. The average time of the oral oxybutynin treatment was 1.5 weeks (3 days to 4 weeks). During the oral therapy these patients complained of the side effects of different magnitude: dry mouth (15 patients--100%), gastro-intestinal disorders (3 patients--20%), drowsiness (1 patient--6.7%). These side effects forced them to stop the oxybutynin oral therapy. After the change of the drug form from oral to the intrarectal one, none of the patients resigned from the treatment. 13.3% of the patients complained of the mild intensity dry mouth. After the one-month therapy period a complete disappearing of the unstable detrusor symptoms was reported by 5 patients (25%), while all others reported their significant reduction. CONCLUSIONS: The intrarectal oxybutynin administration shows the therapeutic efficacy comparable with the intravesical administration with reference to unstable detrusor symptoms reduction. Intrarectal administration reduces the oxybutynin side effects in comparison with the oral one.

Administration, Rectal↗

PubMed1991

Immunoprophylaxis of superficial bladder cancer: a prospective and randomized comparison of oral versus intravesical Bacillus Calmette-Guerin.

A total of 84 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumor. All patients had stage pTa or pT1 transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The patients were assigned to three treatment groups: I. Control group-transurethral resection (TUR-BT) discontinued within the study. II. Oral BCG group-TUR-BT plus BCG (Moreau). III. Intravesical BCG group-TUR-BT plus BCG. Of 9 patients in the control group, 8 (89%) experienced tumor recurrence during a mean follow-up of 20 months. Of the 33 patients in the oral BCG group, 13 patients (39.3%) had recurrence during a mean follow-up of 39 months. Of the 42 patients in the intravesical group, 8 patients (19%) had recurrence in a 30-month mean follow-up. The incidence of complications was higher in the intravesical (33.4%) than in the oral BCG group (24.2%). These results showed that intravesical BCG is a more effective immunotherapy; however, oral BCG can be utilized in patients who do not accept intravesical BCG administration.

Administration, Intravesical↗

PubMed2001

Effects of vitamin D (calcitriol) on transitional cell carcinoma of the bladder in vitro and in vivo.

PURPOSE: Vitamin D (calcitriol) has significant antiproliferative effects on various tumor cells in vitro and in vivo. In the clinical situation a major impediment to systemic administration of calcitriol is the side effect of hypercalcemia. To test the potential usefulness of calcitriol for bladder cancer treatment, we studied the antiproliferative effect of vitamin D on 2 human bladder cancer cell lines, 253j and T-24, in vitro. We also examined the in vivo effects of calcitriol in an animal model of bladder cancer using intravesical administration to avoid the toxicity of systemic calcitriol therapy. MATERIALS AND METHODS: The presence of vitamin D receptors in normal and neoplastic human bladder tissue, and tumor cells T-24 and 253j was determined by immunoblot analysis. Tumor cell proliferation in the presence or absence of calcitriol was determined using a crystal violet assay. Calcitriol induced apoptosis was determined by morphology, polyadenosine diphosphate ribose polymerase cleavage and annexin V binding. In vivo studies were performed by weekly intravesical instillation of calcitriol in female Fischer 344 rats after induction of tumors by N-methyl nitrosourea. Calcitriol administration was started 3 weeks after tumor induction for 7 doses at weekly intervals. RESULTS: Normal and neoplastic human bladder tissue, and the cell lines expressed vitamin D receptors. In the 253j and T-24 cell lines proliferation was significantly inhibited by calcitriol. Progressive cleavage of full length polyadenosine diphosphate ribose polymerase was observed in calcitriol treated cells starting as early as 4 hours after exposure. Similar changes were not observed in the control cells treated with vehicle (ethanol) alone. After 24 hours of treatment with calcitriol 45.8% of 253j cells bound annexin compared to 16.5% of control cells (chi-square p <0.001). Of the control animals 66% developed bladder tumors and 55% of the animals treated with calcitriol early (3 weeks) after tumor induction developed bladder tumors. Almost all of the tumors that developed in the calcitriol group were unifocal, and only 20% were invasive compared to 50% of those in the control animals. CONCLUSIONS: These results demonstrate that calcitriol inhibits proliferation and induces apoptosis in human bladder tumor cells in vitro, and may have therapeutic potential in bladder cancer. In vivo studies using an N-methylnitrosourea induced model of bladder cancer demonstrate that early institution of intravesical calcitriol therapy after carcinogen exposure results in fewer tumors, which are also less likely to be multifocal, high grade or invasive. With our protocol a short course of intravesical calcitriol administration did not result in any significant toxicity.

Administration, Intravesical↗

PubMed1997

Complications of intravesical oxybutynin chloride therapy in the pediatric myelomeningocele population.

PURPOSE: We report our experience with the intravesical administration of oxybutynin chloride with particular focus on the incidence and characterization of untoward effects and inconvenience of therapy. MATERIALS AND METHODS: From 1990 to 1995, 23 children 5 to 11 years old with myelodysplasia were treated with intravesical oxybutynin chloride. Initial dose was 1.25 mg. in 5 cc sterile water instilled during routine catheterization 3 times daily, which was increased as tolerated and clinically indicated. Oral anticholinergic, antispasmodic and sympathomimetic medications were discontinued during therapy. We reviewed therapeutic indications, doses, frequency duration, reason for discontinuation and untoward effects. Patients/parents were surveyed for convenience of treatment as well as side effects and their timing with respect to drug administration and dose. RESULTS: In 15 patients (65%) treatment was discontinued and oral formulations were resumed or other therapy was required due to side effects, ineffectiveness or inconvenience. Seven patients had untoward effects, ranging from facial flushing and dizziness to agoraphobia and hyperactivity. Six patients discontinued therapy due to side effects after 1 day to 2 years (mode 1 month) at doses of 1.25 to 5 mg., including 5 who previously had side effects from oral oxybutynin chloride. Inconvenience of therapy was noted irrespective of the degree of independence of the child for performing intravesical therapy. CONCLUSIONS: Untoward effects and inconvenience are the most common reasons for discontinuing intravesical oxybutynin chloride therapy for neurogenic bladder dysfunction. Children who previously had side effects from oral oxybutynin chloride are more likely to have them during intravesical therapy.

Administration, Intravesical↗

PubMed2004

Effects of ZD6169, a K ATP channel opener, on neurally-mediated plasma extravasation in the rat urinary bladder induced by chemical or electrical stimulation of nerves.

The effects of oral administration of ZD6169, a potassium channel opener, on neurally mediated plasma extravasation in the urinary bladder and urethra were examined in urethane-anesthetized rats. Plasma extravasation was evaluated by measuring the tissue concentration of Evans blue, administered intravenously (50 mg/kg) 15 min prior to removal of tissues. Plasma extravasation was induced by three different stimuli: intravesical administration of either 0.25% acetic acid or 100 microM capsaicin or electrical stimulation of the pelvic nerve on one side (50 V, 10 s trains, 30 Hz intra-train frequency at 1 min intervals for 40 min). ZD6169 (5 mg/kg), administered orally 5 h prior to stimulation, significantly reduced the capsaicin-induced (50% decrease, p<0.05) or the electrical stimulation-induced (58% decrease, p<0.05) plasma extravasation in the bladder, but did not prevent the plasma extravasation in the bladder or urethra induced by intravesical infusion of 0.25% acetic acid. Administration of a K(ATP) channel blocker, glibenclamide (20 mg/kg, iv) 45 min prior to ZD6169 administration blocked the effects of ZD6169 on the electrical stimulation-induced plasma extravasation in the bladder and reduced the effects of ZD6169 on capsaicin-induced plasma extravasation. These findings indicate that ZD6169 (and/or a metabolite) can reduce neurogenic plasma extravasation in the bladder and are consistent with other studies indicating that ZD6169 can activate K(ATP) channels in C-fiber bladder afferents and suppress afferent activity.

Acetic Acid↗