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Biomedical subjects

R D Williams

Publications and source records attributed to R D Williams.

At least 19 recordsLinked to original sources
PubMed2014

A needleless liquid jet injection delivery method for cardiac gene therapy: a comparative evaluation versus standard routes of delivery reveals enhanced therapeutic retention and cardiac specific gene expression.

This study evaluates needleless liquid jet method and compares it with three common experimental methods: (1) intramuscular injection (IM), (2) left ventricular intracavitary infusion (LVIC), and (3) LV intracavitary infusion with aortic and pulmonary occlusion (LVIC-OCCL). Two protocols were executed. First (n&#x2009;=&#x2009;24 rats), retention of dye was evaluated 10&#xa0;min after delivery in an acute model. The acute study revealed the following: significantly higher dye retention (expressed as % myocardial cross-section area) in the left ventricle in both the liquid jet [52&#x2009;&#xb1;&#x2009;4] % and LVIC-OCCL [58&#x2009;&#xb1;&#x2009;3] % groups p&#x2009;<&#x2009;0.05 compared with IM [31&#x2009;&#xb1;&#x2009;8] % and LVIC [35&#x2009;&#xb1;&#x2009;4] %. In the second (n&#x2009;=&#x2009;16 rats), each animal received adeno-associated virus encoding green fluorescent protein (AAV.EGFP) at a single dose with terminal 6-week endpoint. In the second phase with AAV.EGFP at 6&#xa0;weeks post-delivery, a similar trend was found with liquid jet [54&#x2009;&#xb1;&#x2009;5] % and LVIC-OCCL [60&#x2009;&#xb1;&#x2009;8] % featuring more LV expression as compared with IM [30&#x2009;&#xb1;&#x2009;9] % and LVIC [23&#x2009;&#xb1;&#x2009;9] %. The IM and LVIC-OCCL cross sections revealed myocardial fibrosis. With more detailed development in future model studies, needleless liquid jet delivery offers a promising strategy to improve direct myocardial delivery.

Animals↗
PubMed1992

When is intervention warranted?

A chemoprevention trial in prostate cancer would be a formidable but potentially rewarding study. The current status of knowledge of drug interactions with, biomarkers of, and even the natural history of prostate cancer is insufficient to study all levels of men at risk. Currently, the most promising group to study is group I--those men with a high probability of developing prostate cancer but who do not currently have evidence of the disease. This could be a placebo-controlled, prospective and randomized study with the endpoint being clinically-detected prostate cancer. In addition, much may be gained from short-term pilot studies of "chemo-active" agents on morphologic and other biomarkers of prostate cancer initiated immediately before surgical removal. It is hoped that such studies may provide rationale for future efforts directed at preventing progression of premalignant or early prostate cancer lesions.

Anticarcinogenic Agents↗
PubMed1992

Phase 1 trial of oral bropirimine in superficial bladder cancer.

A total of 34 patients with measurable superficial transitional cell cancer of the bladder entered into a phase 1, nonrandomized, noncomparative trial to assess the toxicity of the oral interferon inducer bropirimine. Of the patients 26 were also evaluable for response. The toxicity of bropirimine was minimal. At the 3-month evaluation 6 patients had experienced complete regression of tumor and had negative cytology studies, and 2 had partial responses. The majority of complete responses were in patients with carcinoma in situ only, with most responses seen at higher dose levels. One patient with papillary tumor and carcinoma in situ had a complete response. Some early responses appear to be durable. Most importantly, a high rate of complete response was noted at higher dose levels among patients who had failed prior therapy with bacillus Calmette-Guerin. Further clinical trials of bropirimine in bladder cancer appear warranted.

Administration, Oral↗
PubMed1992

Transport properties of an in situ jejunal reservoir in dogs.

To evaluate partial or total replacement of renal function using gut, we measured in vivo transport of nitrogen metabolites, electrolytes, and water into a jejunal segment configured as a continent reservoir in the dog. Reservoir contents were sampled and analyzed at serial time intervals during a 3-h period after instillation of solution containing (in mM) 40 NaCl, 10 NaHCO3, 220 mannitol, pH 8.5, without or with added urease. At 10 min postinstillation, the amount of urea in the solution without added urease was 3-5 times greater than in the presence of added urease, but accumulation of NH4+ was 14-21 times greater in the solution containing added urease, giving a luminal NH4+ concentration up to 10,000 times that of plasma. In the absence of urease, HCO3- concentration fell to 0, and pH declined to 6 at 3 h; in the presence of urease, HCO3- concentration was 4.5 mM, and pH was 7.8 at 3 h. We conclude 1) urea is secreted by the reservoir; 2) H+ is secreted and/or formed in the reservoir; 3) in the presence of urease, urea hydrolyzed to NH3 is converted to NH4+ by H+ and trapped in the lumen; and 4) in the urease solution, H+ binding by NH3 preserves luminal HCO3-, maintaining the initial pH. Thus the continent jejunal reservoir may supplement or replace impaired renal function.

Animals↗
PubMed1992

Degree of comfort in providing care to PWAs: effect of a workshop for baccalaureate nursing students.

A low-incidence area of HIV/AIDS was the site for this study, which examined baccalaureate nursing students' degree of comfort in providing basic nursing care to people with AIDS (PWAs), and determined the effect of a National Institutes of Health (NIH)-sponsored one-day workshop on HIV/AIDS on this degree of comfort. The pretest-posttest study revealed no statistically significant decrease after the workshop in the amount of discomfort associated with providing basic nursing care to PWAs. However, there were changes in the ranking of nursing procedures following the workshop. Included is a discussion of the workshop's effect on students' comfort level and implications for nurse educators. Ideas for related studies in the area of HIV health care are explored.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Immunotherapeutic alternatives in superficial bladder cancer. Interferon, interleukin-2, and keyhole-limpet hemocyanin.

Interleukin-2, IFNs, and TNF are biologic response modifiers that are part of an intricate network of interacting cytokines released during an immune response. Lack of sufficient endogenous cytokine activity secondary to the immunosuppressive effects of tumor growth may be overcome by direct, local application of biologic response modifiers or immunostimulants such as BCG or KLH. Bacillus Calmette-Guérin remains the most effective immunotherapeutic agent for superficial transitional-cell carcinoma. Although the mechanism of action is unknown, the weight of evidence suggests that local cytokine release is involved in the effector pathway. Recent data have shown that the local application of new single-agent immunotherapies can have an effect on superficial transitional-cell carcinoma and CIS similar to that of chemotherapeutic agents and nearly identical to that of BCG. But, unlike the situation with chemotherapy or BCG, these effects are attended by minimal or no toxicity. Chemotherapy and BCG failures have also shown responses to direct instillation of cytokines. Further understanding of the exact mechanism of action of these agents and of their interaction should lead to the optimal antitumor regimen with the least toxicity. Determining the degree of host immunoresponsiveness and which combination of cytokines or immunotherapeutic or chemotherapeutic agents is most effective for a specific tumor type is the challenge for the future.

Adjuvants, Immunologic↗
PubMed1992

Trabeculodialysis for inflammatory glaucoma: a review of 25 cases.

We reviewed the results following trabeculodialysis in 25 eyes of 22 patients with secondary glaucoma due to chronic anterior uveitis. After 1 year, intraocular pressure (IOP) was uncontrolled (greater than 21 mm Hg) in 11 eyes (44%). Trabeculodialysis controlled IOP (less than 21 mm Hg) in 14 eyes (56%), with an average follow up of 52 months (range, 12 to 151 months). Sixteen eyes (64%) were aphakic, but did no worse than the phakic eyes. One eye developed a subchoroidal hemorrhage 3 days postoperatively which required drainage. No other serious complications were encountered. Trabeculodialysis is a safe procedure which can achieve pressure control in these difficult eyes.

Aphakia↗
PubMed1992

Tumors of the kidney, ureter, and bladder.

Neoplastic diseases of the kidneys and urinary collecting system are relatively common, but when detected early, they have an excellent prognosis. Because gross or microscopic hematuria may be an early harbinger of genitourinary pathology, the primary care physician and internist play an integral role in diagnosing these diseases. A high index of suspicion together with a thorough history, physical examination, and appropriate diagnostic studies will enable the correct diagnosis and improved patient management in most cases.

Humans↗
PubMed1991

Single-dose preoperative systemic cyclophosphamide for the prevention of bladder tumor implantation in F344 rats.

An implantable rat bladder tumor model using the rat transitional carcinoma cell line 4909 was used to evaluate the effect of single-dose, preoperative, systemic chemotherapy on the risk of intravesical tumor implantation. To simulate the clinical setting in which drug levels would be present in both the tumor and the site of implantation, both tumor donor animals and tumor recipients were given a single dose of cyclophosphamide (CY) 1 h prior to tumor harvest and implantation. This protocol resulted in a significant reduction in the incidence of tumor implantation, in tumor volume, and in the incidence of nodal metastases relative to control animals. Dose-response experiments demonstrated that 10 of 139 (7%) animals treated with single doses of CY ranging from 2.5-100 mg/kg developed tumors as compared to 46 of 66 (70%) animals with tumors in the control groups (P less than 0.001). CY doses below 2.5 mg/kg were associated with an increased incidence of tumor implantation (19 of 45, 42%). No lethal toxicity was seen at doses of 50 mg/kg or less. Peak antitumor activity occurred when the CY was administered 1 h prior to tumor implantation as compared to 48 or 24 h before or 1 or 24 h after tumor implantation. Preoperative "chemoprophylaxis" may be an effective strategy for preventing bladder tumor recurrences resulting from tumor implantation.

Animals↗
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

Two new uses of 8-F feeding tube in performing injecting urethrograms.

A modification of a previously described method for visualizing the urethrovesical junction is described. This modification is easier to perform, less messy, and obtains superior images to the method now used. A new method for outlining urethral strictures is also described. Both methods use an 8-F feeding tube.

Catheterization↗
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

Computerized tomography for detection and staging of localized and pathologically defined upper tract urothelial tumors.

Between 1980 and 1989, 94 patients were evaluated for upper tract urothelial tumors. Preoperative computerized tomography (CT) scans and pathology reports were available in 30 patients who also had nephroureterectomy for treatment of transitional cell carcinoma. Retrospective evaluation of these CT scans was done without knowledge of the final pathological status to determine accuracy of tumor detection and staging. Pathological findings were also reviewed and the pathological staging was compared to that of CT. At pathological evaluation the 30 renal units contained 34 grossly visible, distinct papillary tumors: 7 were ureteral and 27 were in the renal pelvis. Of the renal units 8 also contained carcinoma in situ that was not visible on any study. Conventional excretory urograms and/or retrograde or antegrade pyelograms detected 28 (82%) and CT 17 (50%) of the 34 papillary tumors. Excluding suboptimal scans due to early generation machines, inadequate intravenous contrast medium or too widely spaced slices caused CT sensitivity to increase to 15 of 22 (68%). It was not possible to distinguish stages Ta to T2 lesions on any radiological study. CT sensitivity for parenchymal invasion was 75% with a specificity of 43%. CT sensitivity for fat invasion was 67% with a specificity of 44%. We conclude that CT is limited in usefulness for detection and staging of low stage upper tract urothelial tumors. While CT is the best current imaging modality over-all for staging of upper tract urothelial tumors, results obtained in low stage tumors must be viewed with caution particularly when precise preoperative clinical staging is essential, such as before nephron-sparing procedures.

Carcinoma in Situ↗
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

Lymphokine-activated killer traffic assay and our preliminary clinical results of regional arterial infusion of lymphokine-activated killer cells for renal cell carcinoma.

In vivo distribution of radiolabeled lymphokine-activated killer (LAK) cells that were administered either through the caudal vein or the abdominal aorta of Lewis rats was studied. The LAK traffic study showed remarkable increase in radioactivity in several organs peripheral to the arterial injection site. We began treating the patients with metastatic renal cancer by means of regional arterial administration of LAK cells. This treatment was supported by the results of the traffic assay. Our regional LAK therapy, which involves a weekly leukapheresis in combination with daily systemic low dose interleukin-2 administration, has been in practice for over 2.5 years. Seven out of 12 metastatic lesions in the 7 patients treated showed regression. Two responding cases have been alive for over 2 years. Responding lesions were bone, muscle, para-aortic lymph node, and/or retroperitoneum. The regional arterial administration of LAK cells is local therapy. However, this mode of therapy could be useful for those patients with extrapulmonary nonresectable metastasis and at least one injectable feeding artery. This study shows our laboratory data concerning the localization of LAK cells transferred via arterial route and our clinical cases treated with regional arterial administration of LAK cells.

Animals↗