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Biomedical subjects

W A See

Publications and source records attributed to W A See.

70 records · Page 4Linked to original sources
PubMed1991

Single-dose cyclophosphamide for the prevention of bladder tumor implantation in F344 rats: site of drug activity.

Previous studies demonstrated that single doses of systemic cyclophosphamide (CY) as low as 0.5 mg/kg are effective in preventing bladder tumor implantation in a rat model. In an effort to determine if the urinary bladder represents a unique site of CY activity, a series of experiments were performed to define the mechanism by which low-dose CY prevents bladder tumor implantation. Potential sites for CY antitumor activity include direct tumor cytotoxicity resulting from serum delivery of drug to the tumor; tumor cytotoxicity resulting from tissue drug levels at the site of implantation; altered tumor cell adherence to the urothelial injury site; nonspecific urothelial cytotoxicity resulting from urinary excretion of the CY metabolites; tumor cell-specific cytotoxicity resulting from urinary excretion of the CY metabolite acrolein; and second-pass cytotoxicity resulting from urinary excretion of the active form of CY. Experiments were performed to determine if a single predominant site of activity could be defined. Cyclophosphamide levels at the site of tumor implantation appeared to be the most important determinant of antiimplantation activity. Only tumor recipients pretreated with CY had a significant decrease in bladder tumor implantation. In vivo and in vitro assays measuring the effect of blood-borne drug delivery directly to the tumor failed to demonstrate cytotoxic activity. Tumor cell adherence assays measuring in vitro adherence of CY-treated tumor cells and in vivo adherence of tumor cells in CY-treated recipients showed no difference in comparison to control groups. Interval histological comparison of CY-treated and control bladders failed to demonstrate any difference. Urinary levels of acrolein did not contribute to antiimplantation activity. Preimplantation CY doses prevented tumor development in a s.c. implantation model, thereby excluding a second-pass effect resulting from urinary drug excretion. These data suggest that the bladder is not unique in its response to systemic low-dose CY administered for the prevention of implantation-mediated tumor recurrence. Low-dose, perioperative chemoprophylaxis may be applicable to other tumor systems in which intraoperative tumor dissemination is felt to contribute to recurrence risk.

Animals↗
PubMed1991

Regional chemotherapy using continuous intravesical infusion doxorubicin for the treatment of muscle invasive transitional cell bladder carcinoma in a rat model.

Previously established animal models of invasive transitional cell bladder carcinoma and continuous infusion intravesical drug delivery were combined to evaluate the urothelial toxicity and antineoplastic efficacy of continuous intravesical infusion doxorubicin (DOX). Dose-response toxicity experiments studied histologic changes in the rat urinary bladder following urothelial exposure to three different urinary levels of DOX, as a function of the duration of drug infusion. Systemic and local drug absorption, as measured by DOX levels in serum, bladder, retroperitoneal lymph nodes, and liver, was measured at intervals during drug administration. In vitro chemosensitivity assays were used to determine tumor sensitivity to DOX. Treatment studies evaluated the impact of 14-day continuous infusion DOX beginning seven days following tumor implantation. No histologically discernable changes in the normal urothelium were noted in bladders of animals receiving continuous intravesicle DOX at mean urinary concentrations of 0.05 micrograms./ml. (n = 5), 0.56 micrograms./ml. (n = 10), and 5.69 micrograms./ml. (n = 10) for periods of up to 14 days. Serum drug concentrations demonstrated a non-significant upward trend following the start of therapy. Significant increases in tissue DOX levels were noted in the bladder and retroperitoneal lymph nodes on chemotherapy days 7 and 14. Mean tissue DOX concentrations in both the bladder and lymph nodes were greater than the IC50 observed in the in vitro sensitivity assay. DOX-treated tumor-bearing animals (n = 17) had a mean tumor volume (+/- standard deviation) of 0.65 gm. +/- 0.52 gm. compared to an average tumor volume of 1.20 gm. +/- 0.66 gm. in the control group (n = 18) (p = 0.0112). Continuous infusion intraluminal chemotherapy demonstrated a clear cytoreductive effect with minimal local toxicity in this model. Drug tissue levels were observed in regional lymphatic drainage fields as well as the bladder wall. Further study to evaluate this approach as a bladder-sparing alternative to muscle invasive disease is warranted.

Administration, Intravesical↗
PubMed1991

Antimicrobial tissue penetration in a rat model of E. coli epididymitis.

Following induction of unilateral epididymitis by intratesticular injection of E. coli, a single intraperitoneal dose of amdinocillin, ampicillin, doxycycline, tobramycin, or trimethoprim/sulfamethoxazole was administered to five groups of rats. The animal was sacrificed serially and concentrations of antibiotic in serum, infected epididymides, and non-infected epididymides were determined by high performance liquid chromatography. The ratio of infected to non-infected tissue area under the curve values was 1.05 for trimethoprim, 1.58 for sulfamethoxazole, 1.67 for amdinocillin, 2.01 for tobramycin, 2.25 for doxycycline, and 2.58 for ampicillin. Except for trimethoprim, infected tissue concentrations were significantly greater than compared to uninfected epididymal levels (p less than 0.05). Antibiotic concentrations in infected epididymides compared to serum revealed overall penetration of 34% for amdinocillin, 66% for sulfamethoxazole, 70% for ampicillin, 76% for tobramycin, 256% for trimethoprim, and 257% for doxycycline. In a rat model of epididymitis, trimethoprim and doxycycline demonstrated the greatest degree of epididymal penetration compared to serum. All antibiotics except trimethoprim had significantly greater penetration into infected tissue when compared to non-infected epididymal tissue.

Animals↗
PubMed1991

A continuous intravesical drug delivery system for the rat.

We describe a self-contained system for the continuous infusion of drugs into the rat urinary bladder. A reversible model of hydronephrosis is used to prepare one renal unit for nephrostomy tube placement. An 0.8 mm. silastic nephrostomy tube is introduced into the hydronephrotic kidney via a 16 gauge angiocath. The nephrostomy tube is then connected to an Alzet mini osmotic pump which is implanted in a subcutaneous location. The ability of this system to deliver a continuous dose of a test agent into the bladder was evaluated. Pumps were filled with a 1% solution of methylene blue in phosphate buffered saline. Following pump implantation, urinary samples were collected on a daily basis and subsequently analyzed for their concentration of methylene blue. At the completion of the experiment, specimens of the kidney, ureter, and bladder were histologically examined. Results demonstrated an average of 102% recovery of the theoretically delivered dose over a 14-day period. Renal histology demonstrated chronic inflammatory changes at the site of nephrostomy tube placement. No upper or lower tract urothelial changes were identified. This model provides a system for the continuous delivery of drugs in the rat urinary tract and results in no histological alteration to the lower urinary tract.

Administration, Intravesical↗
PubMed1991

Urinary levels of activated trypsin in whole-organ pancreas transplant patients with duodenocystostomies.

Urinary levels of trypsinogen and active trypsin were measured in 34 urine samples from 14 patients an average of 23 months following whole organ pancreas transplantation and duodenocystostomy. Timed urine specimens obtained 30 min and 90 min following a time zero void were collected from 5 patients in an effort to define the kinetics of trypsinogen secretion and activation. Total urinary protein and urinary pH were correlated with urinary levels of trypsin and trypsinogen. Twenty-one specimens from 8 normal volunteers and a single specimen from a pancreas transplant patient with a duodenoenterostomy served as controls. Activated trypsin was present in 33 of 34 specimens from 13 of the 14 transplant patients. The average total trypsin activity in all samples was 84.4 micrograms/ml urine (+/- SE 9.6). Trypsinogen was present in 13 of 34 samples, from 7 of 14 patients. The average trypsinogen concentration of all 34 samples was 9.6 +/- 6.2 micrograms/ml. No trypsin or trypsinogen activity was identified in any control sample. In the 5 patients undergoing timed urine collections total trypsin increased an average of 1.3-fold at 30 min and 1.1-fold at 90 min relative to time zero. Urinary trypsinogen increased an average of 7.1-fold at 30 min and 3.1-fold at 90 min following the initial void. Urinary pH and total urinary protein failed to show a significant correlation with urinary levels of total trypsin or trypsinogen. These data suggest that trypsinogen is rapidly converted to active trypsin following secretion into the bladder, resulting in the high urinary trypsin levels that were detected in the majority of patients.

Cystostomy↗
PubMed1991

Ectopic ureter: a rare cause of purulent vaginal discharge.

We report two cases in which urologic anomalies presented with vaginal discharge and fever in young women, aged 9 and 18 years. Both patients were ultimately diagnosed as having duplicated collecting systems with ectopic upper-pole ureters opening into the introitus. Although congenital urologic anomalies are a rare cause of vaginal discharge in young women, they should be included in the differential diagnosis of patients presenting with these symptoms.

Adolescent↗
PubMed1990

Kinetics of transitional tumor cell line 4909 adherence to injured urothelial surfaces in F-344 rats.

Prior reports have described the mechanism initially responsible for transitional tumor cell adherence and implantation on injured urothelial surfaces. This study further quantifies variables that influence the size of tumor inoculum at the injury site and thereby affect bladder tumor recurrence risk. The surface area of urothelial injury, the concentration of tumor cells in the intravesical bathing medium, the viability of tumor cells, the time of urothelial exposure to tumor cells, and the intravesical pressure were the variables studied. Increasing the surface area of urothelial injury resulted in a linear increase in the size of the tumor inoculum (r2 = 0.805, P = 0.0001). Tumor inoculum increased as a direct function of the concentration of tumor cells in the bathing medium. This relationship was linear at low cell concentrations (r2 = 0.64, P = 0.0001). Higher concentrations of tumor cells appeared to result in saturation of the system, with a relationship best described by a log/log function (r2 = 0.975, P = 0.0001). Viable and nonviable tumor cells appeared to compete for available binding sites with equal efficacy. A simple logarithmic relationship was seen for the effect of exposure time on the size of the tumor inoculum (r2 = 0.513, P = 0.0198). Tumor inoculum increased as a linear function of the intravesical pressure (r2 = 0.314, P = 0.0125). These results demonstrate a significant positive correlation between each of the experimental variables and the size of tumor inoculum. Manipulation of these variables in clinical practice may alter the size of tumor inoculum and thereby have an impact on tumor recurrence secondary to implantation.

Animals↗
PubMed1990

Bacterial epididymitis in the rat: a model for assessing the impact of acute inflammation on epididymal antibiotic penetration.

A rat model of bacterial epididymitis was developed and characterized for use in assessing the impact of acute epididymal inflammation on antibiotic penetration into the epididymis. A 0.2 ml. intratesticular injection of a 0.5 McFarland standard suspension of E. coli resulted in histologically confirmed acute epididymitis in all animals studied. Inflammatory changes were detectable as early as 24 hours following inoculation and were progressive to the last assessment point at 11 days. Early testicular infarction was observed in association with epididymal inflammation. Serial transcrotal ultrasounds of infected animals showed progressive increase in epididymal size and a late decrease in testicular size. Serum and epididymal drug concentrations were assayed following a single dose of the antibiotic amdinocillin. Fifteen minutes following the peak serum level, the drug concentration in infected epididymis was 2.3-fold higher than the contralateral, non-infected epididymis. These data suggest that acute inflammation enhances antibiotic penetration into the infected epididymis. The model described provides a rapid, reproducible method to study epididymal drug delivery in normal and diseased states.

Amdinocillin↗
PubMed1989

Pathophysiology of transitional tumor cell adherence to sites of urothelial injury in rats: mechanisms mediating intravesical recurrence due to implantation.

The mechanism by which transitional tumor cells adhere to areas of urothelial injury and the means by which heparin prevents this phenomenon were studied. Scanning electron microscopy and a radiolabeled tumor cell adherence assay were used to assess the activity of heparin and a "nonglycosaminoglycan" thrombolytic agent, recombinant tissue plasminogen activator, in preventing tumor cell adherence to areas of urothelial injury. Systemically administered heparin and intravesical therapy with recombinant tissue plasminogen activator duplicated the activity of intravesical heparin. Scanning electron microscopy showed tumor cells entrapped at the injury surface in a RBC/fibrin clot, which was prevented by intravesical heparin. These data suggest that clotting cascade activation by urothelial injury is the mechanism by which particulate adherence to the urothelium occurs. Interruption of this process by local or systemic anticoagulation with heparin or shifting of the equilibrium of clot formation/lysis toward thrombolysis with recombinant tissue plasminogen activator prevents tumor cell adherence. Intravesical thrombolytic therapy may represent a new approach to recurrence prophylaxis for superficial bladder carcinoma.

Animals↗
PubMed1988

Scrotal ultrasonography: a predictor of complicated epididymitis requiring orchiectomy.

The decision between continued medical therapy and surgical exploration in patients with complicated epididymitis is difficult. We evaluated scrotal ultrasonography as a noninvasive aid in such problematic cases. During a 48-month period 95 patients were hospitalized for treatment of epididymitis; 23 underwent scrotal ultrasonography and 10 required orchiectomy. Analysis of the 21 cases with abnormal findings demonstrated that orchiectomy was necessary in 1 of the 10 patients (10 per cent) with epididymal enlargement only, in 2 of 8 (25 per cent) with epididymal enlargement plus hypoechoic testes and in all 3 with epididymal enlargement plus testicular inhomogeneity (p equals 0.0099). Patients with progressive testicular changes on serial ultrasound examinations uniformly required orchiectomy (5 of 5). Sonographic findings of testicular inhomogeneity correlated with testicular infarction and findings of decreased testicular echogeneity correlated with acute or chronic orchitis. In the appropriate clinical setting gray scale ultrasonography provides objective information supporting the need for surgical intervention in selected patients with complicated epididymitis.

Epididymitis↗
PubMed1987

Heparin prevention of tumor cell adherence and implantation on injured urothelial surfaces.

Increasing laboratory and clinical evidence supports the concept of tumor cell implantation as a cause of intravesical recurrence in transitional cell carcinoma of the bladder. The integrity of the surface mucopolysaccharide layer of the bladder has been shown to be crucial in preventing bacterial or crystalline adherence. The purpose of this study was to evaluate the effects of bladder surface mucin integrity on tumor cell adherence and implantation. The adherence of tumor cells to in situ bladders which were either normal, injured, or injured and subsequently heparin-coated was studied using a radiolabeled tumor cell adherence assay. The mechanism of action of heparin in reducing tumor cell adherence and cytotoxic effects of heparin on tumor cells were evaluated. Finally, the ability of topical heparin to reduce tumor implantation rates on injured urothelial surfaces was studied. Urothelial injury by either dilute acid or fulguration resulted in markedly increased tumor cell adherence compared to normal. Topical heparin was capable of reducing cell adherence in injured bladders to control levels. Bladder coating with heparin rather than tumor cell coating was found to be the critical determinant in preventing tumor cell adherence. Heparin had no cytotoxic effects in any of the assays used. The implantation rate in heparin coated bladder was 19% compared to 50% in non-coated bladders. This study suggests that the bladder surface mucopolysaccharide layer plays a critical role in preventing tumor cell adherence and subsequent implantation. Restoration of this layer via exogenous topical heparin is capable of restoring the anti-adherence integrity to the bladder surface.

Animals↗
PubMed1987

Tumor cell implantation following neodymium-YAG bladder injury: a comparison to electrocautery injury.

Recent clinical experience using the neodymium-YAG laser for the ablation of superficial bladder carcinoma seems to indicate a decreased local and second-site recurrence rate when compared to standard electrosurgical methods. Altered tumor cell implantation has been suggested as a mechanism explaining this phenomenon. The purpose of this study was to compare the effects of laser ablation and standard electrosurgical resection on tumor implantation. Each of three requisite steps in tumor cell implantation was assayed in an animal model system. The number of viable tumor cells liberated during ablation of a standardized lesion was 620% greater in the electrosurgically resected group compared to the laser irradiated group. No difference was observed in the qualitative or quantitative patterns of cellular adherence to a fulguration bladder injury compared to a laser bladder injury. The number of cells adhering to an injury site was shown to increase as a function of the cell concentration to which it was exposed. There was no difference between groups in occurrence of tumor at the injury site following exposure to an equal number of tumor cells. This study has demonstrated marked differences between electroresection and laser ablation in terms of the number of viable cells released during the course of tumor removal. This data, together with the absence of injury site differences, suggests it may play a role in the clinically observed differences in tumor recurrence rates.

Animals↗
PubMedDate not supplied

Future therapies for the treatment of bladder neoplasms.

The last several decades have witnessed an exponential growth in the understanding of the biology of human neoplasms. As a consequence, a number of new strategies for the treatment of urologic cancers are currently under evaluation. We provide an overview of promising new treatment approaches as they apply to the management of transitional cell carcinoma of the urinary bladder.

Antineoplastic Agents↗