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Results for “Administration, Intravesical”

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PubMed1995

Targeting of bladder cancer with monoclonal antibody NCRC48--a possible approach for intravesical therapy.

OBJECTIVE: To determine the localization of the anti-MUC1 mucin monoclonal antibody (mAb) NCRC48 to bladder cancer following intravesical administration. PATIENTS AND METHODS: mAb NCRC48 (330-500 micrograms) radiolabelled with 111indium (11-17 MBq) was administered intravesically to 12 unselected patients with radiological evidence of bladder cancer. Tumour localization was assessed by gamma-camera imaging and by tissue biodistribution studies on biopsies obtained at cystoscopy at about 2 or 24 h after the procedure. After 24 h, whole blood radioactivity was measured and 3 weeks after the procedure the serum level of human anti-mouse antibodies was estimated using an ELISA method. RESULTS: Eleven patients had tumours confirmed at cystoscopy (grades 1-3, stages pTa-pT2). The mean uptake of NCRC48 by tumour and by normal urothelium (expressed as the percentage of the instilled dose/g x 10(3) +/- SD) at 2 h was 3.42 +/- 3.68 and 0.41 +/- 0.77 (P < 0.05). After 24 h, the values for tumour and normal urothelium were 1.17 +/- 1.18 and 0.17 +/- 0.11, respectively. Areas of increased activity on the scintigrams were consistent with the position of the tumours at cystoscopy. No radioactivity was detected in blood at 24 h and there was no evidence of a human anti-mouse antibody response. CONCLUSION: The MUC1 mucin may be a suitable antigen to study the potential of therapeutic strategies based on monoclonal antibody targeting of superficial bladder cancer and may allow the development of more effective agents in the treatment of this condition.

Aged↗

PubMed1994

Urinary bladder-selective action of the new antimuscarinic compound vamicamide.

1. The inhibitory action of vamicamide (FK176, (+/-)-(2R*,4R*)-4-dimethylamino-2-phenyl-2-(2-pyridyl)valeramide, CAS 132373-81-0) on the responses of various tissues to the cholinergic agonists, carbachol and McN-A-343 (4-[m-chlorophenylcarbamoyloxy]-2-butynyl-trimethylammonium chloride, CAS 55-45-8), was investigated in isolated tissue preparations. Vamicamide showed competitive antagonistic actions against all the preparations tested and its pA2 value for the urinary bladder was 6.82, which was higher than that for the atria (5.94) and almost the same as that for the vas deferens (6.90) and for the stomach (6.81). The pA2 values of oxybutynin hydrochloride (oxybutynin) and atropine sulfate monohydrate (atropine) were nearly the same in all the tissues tested. 2. Oral administration of vamicamide 0.1-1.0 mg/kg inhibited dose-dependently spontaneous bladder contractions caused by raising the intravesical volume in conscious rats. Inhibitory actions were also obtained with 0.32-3.2 mg/kg of oxybutynin or 0.0032-0.032 mg/kg of atropine, but the duration of action of oxybutynin was shorter than that of vamicamide or atropine. Vamicamide further inhibited bladder contractions in rats following intravesical administration of 0.05-0.5 mg/ml solution. 3. Vamicamide had no effect or only slightly inhibited spontaneous motility of the stomach and distal colon in conscious rats, as well as heart rate and salivary secretion in conscious dogs, after oral dosing with 3.2 mg/kg of the compound. Similar results were obtained with oxybutynin, excepting the occurrence of tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Comparison of the mode of action of prostaglandin E2 (PGE2) and sulprostone, a PGE2-derivative, on the lower urinary tract in healthy women. A urodynamic study.

The influence of intravesical administration of PGE2 (1,500 micrograms) and sulprostone, a PGE2 derivative (1,000 micrograms) on urodynamic parameters of the lower urinary tract was tested on six healthy female patients. PGE2 and sulprostone significantly decreased the urethral closure pressure at rest. PGE2 increased the detrusor opening pressure as well as the detrusor pressure during maximum flow. Sulprostone, in contrast, slightly decreased these parameters. Both substances caused a strong urgency sensation resulting in an equally reduced bladder capacity and leading to a measurable bladder instability in both cases. This gives rise to the assumption that frequency, urgency and bladder instability may be the result of intravesical relaxation. By 24 h after administration all urodynamic parameters had returned to pretreatment values, thus indicating that long-term changes in urodynamic parameters are not found after either prostaglandin.

Abortifacient Agents, Nonsteroidal↗

PubMed1992

Tumor necrosis factor and chemotherapeutic drugs targeted at DNA topoisomerase II for the treatment of genitourinary malignancies.

Recombinant TNF as a single agent for human cancer appears to be of limited value. However, rTNF has synergistic anticancer effects when combined with chemotherapeutic drugs targeted at DNA topoisomerase II. This effect of rTNF has been observed in several in vitro and in vivo tumor models, both in animal and human studies. The mechanism of this interaction appears to involve lesions to the DNA of tumor cells mediated by inhibition of DNA topoisomerase II. The combinations of rTNF plus doxorubicin and rTNF plus etoposide administered systemically are currently under evaluation by clinical trials in patients with advanced cancers. Determination of the efficacy of such combination therapy must await the completion of phase I and II trails. Other routes of administration that might increase the local concentration of rTNF and could be combined with topoisomerase II-targeted drugs include intravesical administration and the use of tumor-infiltrating lymphocytes.

Animals↗

PubMed1987

Early intravesical instillation of adriamycin with oral administration of 5-fluorouracil after transurethral resection for superficial bladder cancer: preliminary results.

In all, 199 patients were entered in this study by 21 collaborating hospitals. Patients with superficial transitional cell carcinoma of the bladder were randomized postoperatively into four groups. Group A received early (immediately and 2 days after transurethral resection) instillation of adriamycin (30 mg/30 mg); group B received early instillation of adriamycin with oral administration of 5-fluorouracil (200 mg/day); group C received delayed (7 days after transurethral resection) instillation of adriamycin (30 mg/30 ml); and group D received delayed instillation of adriamycin with oral administration of 5-fluorouracil (200 mg/day). All patients subsequently received instillations weekly for 2 more weeks, and then every 2 weeks for a further 14 weeks. After 4 months, they received one instillation per month for 8 months. 5-Fluorouracil was administered p.o. for 1 year. The postoperative follow-up period was 12 months. After 3 and 6 months there were significant differences in the non-recurrence rates between groups B and C. After 12 months the overall non-recurrence rates were 87.9% in group A, 83.5% in group B, 89.2% in group C, and 82.8% in group D, and there were no significant differences among the four groups. The number of patients entered and the follow-up period are not adequate for firm conclusions, and further studies are necessary. The main side effect was bladder irritation, which was observed in 38.8% of patients in the early instillation groups and in 26.3% of those in the delayed instillation groups. No severe systemic side effects were observed in this study.

Administration, Intravesical↗

PubMedDate not supplied

Prophylaxis of superficial bladder cancer with a modified intravesical epirubicin treatment schedule.

A controlled prospective trial on 99 eligible patients evaluated the efficacy of intravesical epirubicin administration as prophylaxis against tumor recurrences after complete endoscopic resection of superficial bladder cancer. The treatment schedule consisting of an initial 6- or 8-week course of instillations, followed by single maintenance doses (to the responders) at follow-up examinations, was modified in those of the initial responders who were at high risk for recurrence and who received an additional separate 4-week course of therapy. Sixty percent of the epirubicin-treated patients and 41% of the controls (who underwent resection alone) remained free of recurrences for a mean follow-up of 32.1 months, but the difference was not significant. However, in terms of relative risk for recurrences (recurrence rate per 100 patient-months and disease-free interval), comparisons between the two groups of patients revealed a significant benefit of epirubicin, overall as well as for those with a history of previous tumor recurrences, multifocal disease, and stage Ta and grade 2 neoplasms. Drug-induced toxicity was acceptable.

Administration, Intravesical↗

PubMed1991

Evidence of significant absorption of sodium salicylate from urinary bladder of rats.

The hypothesis that weakly acidic drugs are reabsorbed from the urinary bladder was tested using adult female Fischer rats. Bladder reabsorption would have direct implications for pharmacokinetic data analysis of compounds with significant renal excretion. Sodium salicylate (SA) undergoes extensive renal excretion in the rat, and was selected as the model compound. Methodology was developed to administer an intravesical dose to a rat via a transurethral catheter. The barrier function and the integrity of the bladder urothelium were examined by light and electron microscopy, and by monitoring leakage of [14C] inulin (MW 5000) and fluorescein (MW 376). Using these methodologies, we found that urothelial integrity was maintained in about 80% of the animals. Animals that showed tissue damage were excluded from the study. In the pharmacokinetic experiments, one group of animals received an i.v. dose of SA (1.5 or 3 mg/kg), the second group received an intravesical dose of 30 mg/kg (approximately 0.3 ml) and the third group received concomitantly an i.v. tracer dose of [14C] SA and an intravesical dose of unlabeled SA (30 mg/kg). The intravesical dose was removed after 90 min. The intravesical administration of SA produced maximal blood concentrations of 10.8 +/- 5.6 micrograms/ml (mean +/- S.D., n = 10) at 90 to 100 min. The fraction of the intravesical dose recovered after 90 min was between 45 and 75%, which indicates an upper limit of 25 to 55% loss by processes including absorption. The bioavailability of the intravesical dose, calculated from the blood data and the clearance of the i.v. doses, was between 4 and 23% and averaged about 13%.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

PubMed2001

A novel strategy for NQO1 (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) mediated therapy of bladder cancer based on the pharmacological properties of EO9.

The indolequinone EO9 demonstrated good preclinical activity but failed to show clinical efficacy against a range of tumours following intravenous drug administration. A significant factor in EO9's failure in the clinic has been attributed to its rapid pharmacokinetic elimination resulting in poor drug delivery to tumours. Intravesical administration of EO9 would circumvent the problem of drug delivery to tumours and the principal objective of this study is to determine whether or not bladder tumours have elevated levels of the enzyme NQO1 (NAD(P)H:quinone oxidoreductase) which plays a key role in activating EO9 under aerobic conditions. Elevated NQO1 levels in human bladder tumour tissue exist in a subset of patients as measured by both immunohistochemical and enzymatic assays. In a panel of human tumour cell lines, EO9 is selectively toxic towards NQO1 rich cell lines under aerobic conditions and potency can be enhanced by reducing extracellular pH. These studies suggest that a subset of bladder cancer patients exist whose tumours possess the appropriate biochemical machinery required to activate EO9. Administration of EO9 in an acidic vehicle could be employed to reduce possible systemic toxicity as any drug absorbed into the blood stream would become relatively inactive due to an increase in pH.

Antineoplastic Agents↗

PubMed2001

[Therapeutic advances of nuclear medicine in oncology].

With the development of new radiopharmaceuticals there is a tendency to apply nuclear medicine therapy for malignancies of higher incidence (lymphoma, prostate) than the ones which have been treated for many years (thyroid cancer, neuroendocrine tumours). One of the most important areas of current development in radionuclide cancer therapy is the monotherapeutic use of new or already available radiopharmaceuticals in preclinical or phase I studies and to a lesser degree in phase II trials. In this context, the radioimmunotherapy is showing important advances in the treatment of medullary thyroid carcinoma, malignant lymphomas en brain tumours with potential extension to neuroblastoma therapy. The development of DOTA as a chelating agent has lead to the use of Y-90-DOTATOC in the treatment of neuroendocrine tumours, particularly carcinoid tumours, and non-I131I-avid thyroid carcinomas. In an effort to improve tumour targeting together with simultaneous reduction of physiological organ uptake, 131I-MIBG is being used in combination with interferon a and pre-targeting with unlabelled MIBG in the treatment of carcinoid tumours. New routes of administration of radiopharmaceuticals (intratumoral, intra-arterial) have enhanced the treatment of malignancies of liver, pancreas and brain as well as the potential use of radioimmunotherapy by intravesical administration for bladder carcinoma. Another significant tendency in radionuclide therapy is its evolution from monotherapy towards a combined application with other anticancer modalities. Some recent examples of combined therapy with demonstrated anti-tumour effect are found in neuroblastoma (131I-MIBG and chemotherapy), bone metastases of prostatic carcinoma (addition of 89Sr to chemotherapy schedules), brain malignancies (adjuvant use of radioimmnunotherapy in relation to surgery and external radiotherapy) and lymphoma (radioimmunotherapy combined with chemotherapy or immunotherapy). Reinforcing this trend in phase II and III studies as well as the planning of multicenter trials following the guidelines and criteria of clinical oncology will determine the future advances in this field.

3-Iodobenzylguanidine↗

PubMed2006

A role for pituitary adenylate cyclase activating polypeptide (PACAP) in detrusor hyperreflexia after spinal cord injury (SCI).

Intrathecal administration of the PAC1 receptor antagonist, PACAP6-38 (10 nM), significantly (P < or = 0.05) reduced intermicturition, threshold and micturition pressures in chronic (3-6 weeks) spinal cord injured rats but intravesical administration (100-300 nM) was without effect. Intrathecal PACAP6-38 reduced the number and amplitude of nonvoiding bladder contractions observed after spinal cord injury (SCI). PACAP may contribute to detrusor hyperreflexia induced by SCI and PACAP antagonists may be a novel approach to reduce detrusor hyperreflexia after SCI.

Animals↗

PubMed1984

[Intravesical chemotherapy for superficial bladder tumors].

Intravesical chemotherapy is one of the most effective treatments for superficial bladder tumors. Recent progress in the development of chemotherapeutic agents has provided a variety of compounds of potential benefit for intravesical administration in cases of superficial bladder tumors, including thio-TEPA, MMC, carboquone, adriamycin, FT-207, cytosine arabinoside and bleomycin, and the in therapeutic effectiveness has been reported. We selected adriamycin, because it is considered suitable for intravesical instillation. A 68% effectiveness has been experienced for instillation repeated six to nine times (adriamycin 50 mg/normal saline 30 ml) and side effects occurred in 23% of patients. Intravesical chemotherapy has also been attempted to prevent recurrence after conservative therapy but these modalities still seem to need further study.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Bioavailability of trospium chloride after intravesical instillation in patients with neurogenic lower urinary tract dysfunction: A pilot study.

Oral drug treatment of detrusor overactivity often causes undesirable side effects in other organs. For some patients, in particular those with neurogenically induced detrusor overactivity (detrusor hyperreflexia), the tolerance level for adverse effects is low and oral treatment may become ineffective. Intravesical administration of the drug can diminish the side effects or increase treatment effectivity in patients who are (partially) refractory to oral treatment because the relative concentration of the drug is increased in the target organ and decreased in the circulation. Six men (19-34 years old) with traumatic spinal cord lesions between C2 and Th11 were randomized to intravesical instillation with 15 or 30 mg trospium chloride in 40 ml saline into the empty bladder. Catheterization was postponed until at least 3 h after instillation, and fluid intake was not allowed during the first 4 h. Blood samples were taken before and 11 times after instillation; the last sample 12 h post instillation. Four positive samples were found in three patients: 0.10 ng/ml after 1 h and 0.13 ng/ml after 2(1/2) h in two patients with 15 mg, and 0.24 ng/ml after 30 min and 0.70 ng/ml after 6 h in one patient with 30 mg instilled trospium chloride. Three adverse effects were reported and were rated as probably not related to the drug. It is concluded that intravesically instilled trospium chloride is not absorbed into the circulation in significant amounts and, thus, it may be expected that this mode of administration will improve the efficacy of trospium chloride therapy by reducing the side effects. Neurourol. Urodynam. 18:447-453, 1999.

Adult↗

PubMed1985

Treatment of patients with transitional cell carcinoma of the urinary bladder with intravesical poly I: poly C effects on natural killer function.

Considerable interest has been focused on the use of interferon (IFN) and IFN-inducers as antineoplastic agents in humans. The current report will focus on the effect of intravesical administration of Poly I: Poly C on NK activity in patients with TCC of the urinary bladder. NK cytotoxicity was measured in 14 patients with primary TCC, 8 patients received Poly I: Poly C and 5 other patients received intravesical thiotepa. Blood samples were obtained prior to and 48 h following each drug treatment. A variation in the initial NK level determined prior to treatment was observed in the different TCC patients: 5 patients treated with Poly I: Poly C and 5 patients treated with thiotepa exhibited low NK activity prior to treatment, whereas the other 3 patients who were treated with Poly I: Poly C had high initial NK levels. Following drug treatment it was shown that a significant elevation in the NK cytotoxicity was only observed in patients treated by intravesical Poly I: Poly C who had low NK activity prior to treatment. No such effect was observed in patients treated with thiotepa or in patients treated with Poly I: Poly C who exhibited a high NK activity prior to treatment.

Adult↗

PubMed1999

Induction of superficial bladder tumors in the female Fischer 344 rats with AY-27 tumor cells for the study of diffusion and localization of hemoglobin derived components (hematoporphyrin derivative) in view of photochemotherapy.

Photochemotherapy (PCT) consists in administration of a photosensitizer and subsequent irradiation of the tumor with visible light. Routinely, the photosensitizer is given intravenously (i.v.), but the major drawback of this procedure is the resulting skin photosensitivity. The goal of our study is to examine whether intravesical (i.b.) instillation of the photosensitizer for PDT of bladder cancer might be feasible in order to target the tumors and to avoid the photosensitization phenomenon. After first studying the biodistribution of hematoporphyrin derivative (HpD) in vivo in the rat bladder, two and four hours after intravesical administration, by fluorescence microscopy, we compared two different methods for the induction of superficial bladder tumors in rats with AY-27 tumor cell line in order to perform the same study on bladder tumors. The best results for the penetration depth of HpD in the normal bladder wall were obtained two hours after the bladder instillation where the photosensitizer was detected only in the bladder surface (urothelium and small part of the chorion). That's why we must choose the most appropriate bladder tumor model in order to obtain superficial bladder tumors that mimic the clinical behavior of superficial bladder cancer in man. Both techniques used in this study gave a high tumor take rate in a short time (> 90%). But we really obtained superficial bladder tumors directly attached to the bladder surface with one of the two methods of tumor induction consisting in the abrasion of the bladder surface prior to the administration of the tumoral cells in the bladder cavity.

Animals↗

PubMed1984

Mitomycin C reused: an in vitro cost-effectiveness study.

The use of mitomycin C, an effective agent in the intravesical treatment of superficial bladder cancer, is limited by its high cost. An in vitro study was done to determine whether mitomycin C could be recovered after intravesical administration and reused in the same patient. Cultured human transitional carcinoma cells from line 253-J were exposed to: medium alone; fresh mitomycin C (1 mg./ml.); mitomycin C stored for 1, 2 and 4 weeks; and mitomycin C recovered from patients after intravesical use, tested immediately and stored and tested after serial dilution after 1, 2, and 3 weeks. Results were assessed by cell counts 2 and 5 days after 2-hour exposure to the test solutions. With fresh mitomycin C and that stored up to 4 weeks, cell growth was less than 1 per cent of control (medium alone) at 2 and 5 days. Mitomycin C was also effective when recovered after intravesical use for up to 2 weeks, at which time cell growth was 9.7 and 3.1 per cent of control at 2 and 5 days, respectively. However, at 3 weeks, cell counts were 11.5 and 18.3 per cent of control at 2 and 5 days, suggesting that mitomycin C loses potency with dilution. We conclude that mitomycin C might be recovered, stored and reused for at least 2 weeks in individual patients, a practice that could result in a substantial reduction of treatment cost.

Antibiotics, Antineoplastic↗

PubMed1997

Pharmacological biocompatibility between intravesical preparations of BCG and interferon-alpha 2B.

PURPOSE: To determine if BCG and interferon alpha-2B are mutually compatible as mixed intravesical agents for clinical bladder cancer therapy. MATERIALS AND METHODS: Mutual compatibility was assessed by measuring IFN-alpha's effect on BCG metabolic activity, growth rate, and clumping tendency and conversely by observing BCG's effect on IFN-alpha's anti-viral activity. Optical density at 600 nm. (OD600) was used to estimate the number of colony forming units of BCG in suspension during 3 hours measurements of clumping and 8 days measurements of BCG proliferation. BCG viability was evaluated using a substrate marker, MTT, which correlates with BCG density and metabolic activity. The anti-viral activity of IFN-alpha was determined in a cytopathic protection bioassay using the encephalomyocarditis virus/FS-4 cell system. RESULTS: Continuous shaking of reconstituted BCG for 3 hours at 37C resulted in a marginal (11.3%) drop in OD600 which was minimally altered by inclusion of IFN-alpha at 2 million units (MU)/ml. (12.7% drop). Metabolic activity and growth rate of BCG alone or BCG with IFN-alpha were essentially identical. IFN-alpha's antiviral activity was not affected by incubation with BCG. CONCLUSIONS: The inclusion of IFN-alpha into the usual BCG formulation for intravesical administration has no apparent effect on BCG's viability or tendency to form clumps in suspension. Similarly, the physical mixing of IFN-alpha with BCG does not impair its biological activity. Thus, both agents are pharmacologically compatible for future clinical studies involving combination intravesical therapy.

Adjuvants, Immunologic↗

PubMed1996

The effect of NG-monomethyl-L-arginine on bladder function.

Recent studies have demonstrated the presence of nitric oxide synthase (NO synthase) in lower urinary tract tissues, however, its role in the detrusor is unclear. The current study was designed to determine if NO synthase inhibition alters detrusor activities, including micturition volume threshold, and inhibition of pelvic nerve-evoked contractions by various stimuli. In naive, anesthetized adult cats, inhibition of pelvic nerve-evoked bladder contractions, induced by hypogastric nerve stimulation or the intraarterial administration of NA, ATP, adenosine, beta,gamma-methylene ATP and 2-methylthio ATP, was measured before and after inhibition of NO synthase. The micturition volume threshold was also measured before and after NO synthase inhibition. L-NMMA decreased the micturition volume threshold by 38% (2 mg intravesical administration) or 80% (4 mg/kg i.a.). The magnitude of the micturition contractions was modestly increased. These results, and information in the literature, indicate that NO may play a role in the collection phase of the bladder cycle and any alteration of nitric oxide availability could induce or allow development of various bladder malfunctions, such as small bladder diseases, like interstitial cystitis.

Animals↗

PubMed1997

Capsaicin inhibits detrusor contractility but not the micturition reflex in capsaicin-desensitized rats.

Intravesical capsaicin at high concentration (1 mmol/L) inhibits the micturition reflex and detrusor contractility. To investigate the mechanism, we compared rats that had been desensitized by capsaicin at birth with control rats. In vivo cystometrography was performed with normal saline (n = 5) or 1 mmol/L capsaicin (n = 5), then an isolated whole bladder contractility study with electrical field stimulation, bethanechol, and KCl was carried out. In the bladders with normal saline cystometrography and after isolated bladder study, 0.5 mL of 1 mmol/L capsaicin was instilled into the bladders and another set of stimulations by electrodes, bethanechol, and KCl was given. The bladders of capsaicin-desensitized rats showed the presence of detrusor reflexes but diminished amplitudes of detrusor contractions. There was no urinary retention or increased intravesical pressure in these desensitized bladders after capsaicin cystometrography. The detrusor contractility in the isolated whole bladder study showed no significant difference between the control and experimental bladders. After 1 mmol/L capsaicin cystometrography the bladders had little contractility compared with bladders after saline cystometrography. The bladders of the desensitized rats increased in weight compared to the controls. Intravesical administration of 1 mmol/L capsaicin induced an initial excitatory effect on the micturition reflex and final urinary retention in control rats. After capsaicin treatment at birth, these effects no longer existed but the depressant effect of capsaicin on detrusor contractility persisted. We conclude that a high concentration of intravesical capsaicin acutely inhibits the micturition reflex and detrusor contractility. Neonatal desensitization by capsaicin can depress the detrusor contractility in rats but the micturition reflex is not affected.

Animals↗