Biomedical subjects

W J George

Publications and source records attributed to W J George.

At least 19 recordsLinked to original sources

PubMed1999

Differences in cadmium transport to the testis, epididymis, and brain in cadmium-sensitive and -resistant murine strains 129/J and A/J.

Although most animals with scrotal testes are susceptible to cadmium-induced testicular toxicity, strain-related differences are seen in mice. Resistant murine strains demonstrate a decreased cadmium concentration in the testis and also in the epididymis and seminal vesicle. In this study we analyzed cadmium transport into tissues with a vascular barrier, the testis, epididymis, and brain, in an attempt to characterize the mechanisms of strain resistance to cadmium-induced testicular toxicity. In the resistant murine strain A/J, 109Cd transport (administered as 109CdCl2) was significantly attenuated in the testis, epididymis, and brain, when compared to the sensitive murine strain 129/J. The unidirectional influx constant (Ki, in microliter g-1 min-1) for 109Cd was 0.01929 in the A/J testis as compared with 1.174 in the 129/J testis (P <.0001). The percentage of a 109Cd dose that reached the A/J testis by 60 min was over 10 times less than that which reached the 129/J testis. The transport system used by cadmium in the 129/J testis was saturable, with 20 microM unlabeled cadmium chloride inhibiting transport by over 60%. The transporter was competitively inhibited by zinc (P =. 00017), but not by calcium, indicating a specificity in ion transport. Studies with isolated tubules and analysis of testicular fluid compartments demonstrated no significant difference in cadmium uptake or efflux between the strains when corrected for the amount of 109Cd entering the testis. Therefore, murine strain differences in testicular sensitivity to cadmium appear to be related to the variable presence of a transport system for cadmium in the testicular vasculature.

Animals↗

PubMed1998

Murine strain differences and the effects of zinc on cadmium concentrations in tissues after acute cadmium exposure.

The role of strain differences in cadmium tissue distribution was studied using sensitive (129/J) and resistant (A/J) mice. These murine strains have previously been shown to differ in their susceptibility to cadmium-induced testicular toxicity. Cadmium concentration was measured in testis, epididymis, seminal vesicle, liver, and kidney at 24 h after cadmium chloride exposure (4, 10, and 20 micromol/kg CdCl2). The 129/J mice exhibited a significant increase in cadmium concentration in testis, epididymis, and seminal vesicle at all cadmium doses used, compared to A/J mice. However, cadmium concentrations in liver and kidney were not different between the strains, at any dose, indicating that cadmium uptake is similar in these organs at 24 h. These murine strains demonstrate similar hepatic and renal cadmium uptake but significantly different cadmium accumulation in the reproductive organs at 24 h. The mechanism of the protective effect of zinc on cadmium toxicity was studied by assessing the impact of zinc acetate (ZnAc) treatment on cadmium concentrations in 129/J mice after 24 h. Zinc pretreatment (250 micromol/kg ZnAc), given 24 h prior to 20 micromol/kg CdCl2 administration, significantly decreased the amount of cadmium in the testis, epididymis, and seminal vesicle of 129/J mice, and significantly increased the cadmium content of the liver after 24 h. Cadmium levels in the kidney were unaffected at this time. Zinc pretreatment also prevented the cadmium-induced decrease in testicular sperm concentration and epididymal sperm motility seen in 129/J mice. These findings suggest that the differences in the two murine strains may be attributed partly to the differential accumulation of cadmium in murine gonads. This may be caused by strain differences in the specificity of cadmium transport mechanisms. The protective role of zinc in cadmium-induced testicular toxicity in the sensitive strain may be due to an interference in the cadmium uptake by susceptible reproductive organs.

Animals↗

PubMed1997

Metal accumulation in crayfish, Procambarus clarkii, exposed to a petroleum-contaminated Bayou in Louisiana.

Red swamp crayfish (Procambarus clarkii) were placed for a period of 7 days in Bayou Trepagnier, a Louisiana waterway which received petroleum-laden effluents from a manufacturing complex several decades ago. However, coolant water from the plant continued to be released into the bayou until 1995. Analyses of sediments at the exposure site revealed heavy contamination by lead, chromium, and copper, while concentrations of arsenic and cadmium were very low. Significant bioaccumulation of lead was observed in the hepatopancreas and gills of 7-day-exposed crayfish, whereas chromium accumulated the most in the gills and blood. Concentrations of copper in the crayfish did not change during the course of the study, suggesting that this essential metal constituent of the respiratory pigment is successfully regulated even when crayfish are exposed to relatively high levels of copper in the sediments. There was no metal accumulation in the abdominal muscle of the crayfish. That damage to the hepatopancreas occurred during the exposure is suggested by histopathological studies which revealed swollen and vacuolated R cells and an increase in the pH of the digestive juices. Blood glucose levels, as well as ovarian and hepatopancreatic indices, were unchanged. This study demonstrates that accumulation of nonessential metals in crayfish tissues in a wetland environment contaminated by mixed pollution (metals and hydrocarbons) reflects the concentrations of metals in the sediment.

Animals↗

PubMed1996

Regional chemotherapy for inoperable pancreatic carcinoma.

BACKGROUND: Survival for adenocarcinoma of the pancreatic remains unchanged over the last two decades. The majority of patients (85%) are diagnosed with an inoperable tumor. Patterns of failure reveal that pancreatic cancer involves three compartments: the pancreatic bed and regional lymph nodes, the liver and the peritoneal surfaces. Twelve patients with advanced, unresectable pancreatic cancer, Stage II/III, were treated with regional intra-arterial chemotherapy and extracorporeal hemofiltration directed towards the pancreatic tumor-bearing area and the liver. METHODS: Five patients had an arterial catheter/port system placed within the celiac axis; the rest had an angiographically placed arterial catheter. All patients had a 16 Fr PFM filtration catheter inserted in the vena cava positioning the tip at the level of the diaphragm and then connected to a hemofiltration unit. Mitomycin C was infused over 25 minutes followed by 5-FU over 10 minutes. The hemofiltration was begun before the drug infusion and continued for 70 minutes. The twelve patients underwent 33 cycles of regional chemotherapy plus hemofiltration. RESULTS: Five patients had a partial response (45.5%), five had stable disease (45.5%), and one had progression (9%). Four patients were re-explored with one patient undergoing a curative resection. The average survival for patients with unresectable pancreatic adenocarcinoma is 13 months. Tumor implantation and progression on the peritoneal surfaces remains the major site of treatment failure. CONCLUSIONS: Regional chemotherapy plus hemofiltration with MMC and 5-FU appears to improve the response of Stage II/III inoperable pancreatic cancer and can convert some patients to resectability without significant complications and with no mortality.

Adenocarcinoma↗

PubMed1995

Urinary excretion of 6-hydroxychlorzoxazone as an index of CYP2E1 activity.

OBJECTIVE: To determine whether the urinary excretion of 6-hydroxychlorzoxazone is an index of CYP2E1 activity in vivo. METHODS: Male volunteers (n = 27; age range, 17 to 36 years) who were abstinent from alcohol were studied. Chlorzoxazone, 500 mg, was given orally and plasma was collected at 31/2, 41/2, 51/2, and 61/2 hours after dosing. Urine was collected for 8 hours. Ten volunteers participated in full kinetic studies to define the absorption phase and plasma area under the concentration-time curve of chlorzoxazone and the urinary kinetics of the 6-hydroxy metabolite. Chlorzoxazone and the 6-hydroxy metabolite were measured by high-performance liquid chromatography. CYP2E1 activity was expressed as a hydroxylation index (HI = mmole oral chlorzoxazone dose/mmole 6-hydroxychlorzoxazone in 8-hour urine). RESULTS: There was a significant positive correlation between plasma elimination rate constant for chlorzoxazone (Ke) and urinary excretion of the metabolite (n = 27, r = 0.42, p < 0.03) and a significant negative correlation between plasma Ke and HI (n = 27, r = -0.41, p < 0.04). The mean absorption rate constant for chlorzoxazone of 3.11 +/- 4.67 hr-1 was fivefold greater than the plasma Ke of 0.57 +/- 0.17 hr-1 for the full kinetic studies. The formation clearance of the 6-hydroxy metabolite was negative between plasma Ke of the parent compound and disposition rate constant for urinary excretion of the 6-hydroxy metabolite (n = 15, r = 0.85, p < 0.0001). CONCLUSIONS: The urinary excretion of 6-hydroxychlorzoxazone is limited by formation rate and may be useful as an in vivo probe of CYP2E1 activity.

Adolescent↗

PubMed1994

Regulation of metallothionein mRNA in human hepatoma (HEP3B) cells.

PURPOSE: Metallothionein (MT) has been shown to protect cells from the injurious effects of ionizing radiation. MT is an inducible protein and heavy metals can upregulate transcription of the MT gene. The present study was initiated to investigate regulation of MT mRNA synthesis in a human hepatocellular carcinoma (Hep3B) cell line. METHODS AND MATERIALS: MT levels in Hep3B cells were measured by the cadmium-hemoglobin assay. Zinc acetate was used as an inducing agent. Levels of the MT mRNA were determined by the slot blot hybridization technique. Cycloheximide was used as an inhibitor of protein synthesis and actinomycin D was used to block transcription. RESULTS: Zinc acetate (0.1 mM) treatment increased the intracellular levels of MT in Hep3B cells. MT levels peaked at 10 h and remained stable for up to 48 h. A time-dependent increase in the MT mRNA was also observed peaking at 16 h and then declining. Addition of cycloheximide and zinc acetate simultaneously, resulted in a decrease in the levels of MT, whereas MT mRNA levels were increased. There was no significant change in the decay rate of MT mRNA when the cells were treated with actinomycin D (7.5 micrograms/ml) either in the presence or absence of Zn. CONCLUSION: These results suggest that neither the increased synthesis of a metal regulatory factor (MRF) nor an increase in half-life of MT mRNA is involved in the mechanism of increased MT biosynthesis upon addition of Zn. These findings support the hypothesis that a preexisting MRF must complex with Zn to initiate increased transcription for MT.

Carcinoma, Hepatocellular↗

PubMed1994

Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus.

Zidovudine is metabolized to an inactive 5'-glucuronide and has a short plasma half-life requiring frequent dosing. The present study in six patients without symptoms who were infected with human immunodeficiency virus was undertaken to determine if coadministration of valproic acid which, like zidovudine, is metabolized by glucuronidation, would alter zidovudine disposition. Under steady-state conditions for both drugs, the plasma area under the curve for zidovudine increased twofold with a corresponding decline in its oral clearance when given with valproic acid. The mean 5'-glucuronide/zidovudine urinary excretion ratio was reduced by more than 50%, and the amount of unconjugated zidovudine recovered in urine increased by more than twofold. There was no significant increase in the plasma half-life of zidovudine. The effects of valproic acid on zidovudine glucuronidation were related to plasma valproic acid concentrations. Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability.

Adult↗

PubMed1993

High-pressure liquid chromatography/electrochemical detection method for monitoring MDA and MDMA in whole blood and other biological tissues.

The drug Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) is one of several hallucinogenic amphetamine derivatives reported to be serotonergic neurotoxins. The following is a description of a new high-pressure liquid chromatographic (HPLC) analytical method for the analysis of MDMA, 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDE) from whole blood. Upon separation of MDMA, MDA and MDE by HPLC, quantitation is achieved by use of electrochemical detection. Retention times for MDA, MDMA, and MDE are 6.5, 9.2, and 10.3 min, respectively, allowing for a complete chromatographic run every 15 min. The sensitivity of the method is 1 ng/ml which allows for measurement of MDA, MDMA, or MDE in microsamples of whole blood. The volume of blood required is very small (200 microliters); therefore, there is minimal blood loss in repeated blood sampling from small animals. Assay linearity was demonstrated from 1 ng/ml to at least 1 microgram/ml. The coefficients of variation for both intra-assay and inter-assay comparisons were less than 9%. Other HPLC methods have been previously described for the analysis of amphetamine derivatives, but this new method offers greater sensitivity, rapid turn-around time and ease of use.

3,4-Methylenedioxyamphetamine↗

PubMed1993

Protective action of zinc against cobalt-induced testicular damage in the mouse.

The purpose of this study was to determine if toxic effects of cobalt on the murine testis could be prevented by zinc, an essential metal for spermatogenesis. CD-1 male mice were administered one of the following in their drinking water: 1) 400 ppm CoCl2, 2) 800 ppm ZnCl2, 3) 400 ppm CoCl2 + 800 ppm ZnCl2, or 4) distilled water. After 13 weeks, animals were sacrificed and testes were excised, weighed, and processed for histologic study. Comparison of testicular weights revealed no difference between the control and zinc-treated groups, while there was a small but significant reduction in the zinc/cobalt-treated group, and a large reduction in the cobalt-treated group. Histologic evaluation of testes confirmed the degenerative effects of cobalt, as well as the normal morphology in the zinc-treated group. Furthermore, 90% of the animals in the zinc/cobalt-treated group exhibited complete or partial protection as demonstrated by tubular morphology. This study indicates that zinc prevents cobalt-induced testicular damage.

Animals↗

PubMed1993

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.

Animals↗

PubMed1993

Electrophysiological effects of high cocaine concentrations on intact canine heart. Evidence for modulation by both heart rate and autonomic nervous system.

BACKGROUND: Previous clinical reports have suggested that cocaine intoxication may produce severe ventricular arrhythmias due to a direct effect on the heart. However, the effects of high plasma levels of cocaine on the electrophysiology of the heart have not been well characterized and remain poorly understood. METHODS AND RESULTS: The purpose of this study was to characterize the electrophysiological effects of high doses of cocaine on the in situ dog heart. In dogs anesthetized with morphine and alpha-chloralose, cocaine (2-11 micrograms/mL) increased both atrial and ventricular refractory periods and produced rate-dependent increases in atrial, atrioventricular, His-Purkinje, and ventricular conduction intervals. The time constant for the onset of cocaine's conduction slowing effect following a reduction in pacing cycle length from 400 to 260 msec was approximately two beats, and the time constant for diastolic recovery from conduction slowing was approximately 200 msec, which are similar to values reported for several class Ib antiarrhythmic drugs. Cocaine produced a rate-dependent increase in QT interval that was greatest at high heart rates yet produced no change in the ST (QT-QRS) interval. This suggests that high plasma levels of cocaine delay repolarization primarily via slowing of conduction. Cocaine's effects on both atrioventricular and intraventricular conduction were significantly larger in autonomically blocked than in autonomically intact animals. CONCLUSIONS: We conclude that high plasma levels of cocaine, similar to those reported in autopsy reports following fatal cocaine overdose in humans, produce significant rate-dependent conduction slowing effects on atrial, atrioventricular, and ventricular conduction in the in situ heart. These rate-dependent effects are intensified following autonomic blockade.

Animals↗

PubMed1992

Histopathology of testes from mice chronically treated with cobalt.

Effects of cobalt on murine testes were evaluated by light and electron microscopy. Continuous exposure of male mice to cobalt (400 ppm) via drinking water over a 13-week period resulted in a reproducible, sequential pattern of seminiferous tubule degeneration. Initial changes involved vacuolation of Sertoli cells and formation of abnormal spermatid nuclei. This was followed by the presence of multinucleated cells and sloughing of cells. Sertoli cells phagocytosed degenerating cells. Continued degeneration resulted in shrinkage of tubules with the accumulation of "calcified" necrotic debris in some. Sertoli cells were the last surviving cells. As degenerating tubules shrank, peritubular areas became highly disorganized. Myoid cell shapes became irregular, and basal laminae became highly folded. Endothelial cells of testicular vessels were thickened in areas and contained vesiclelike structures. Leydig cell morphology was normal but interstitial areas appeared hypercellular. The possible interactions of cobalt with iron and zinc, essential metals for spermatogenesis, are discussed.

Animals↗

PubMed1992

Cavernous tissue antibiotic levels in penile prosthesis surgery.

A comparison of the delivery of several antibiotics (vancomycin, gentamicin and aztreonam) to the tissue site of prosthesis implantation was studied using cavernous tissue levels for each antibiotic. A total of 32 patients underwent penile prosthesis implantation. Intravenous antibiotics were administered 1 to 2 hours preoperatively, with vancomycin and aztreonam given to patients at the Tulane University Medical Center, and vancomycin and gentamicin given to patients at the New Orleans Veterans Administration Hospital. At operation the urine, serum and cavernous tissue were concurrently sampled and later analyzed for antibiotic concentration. The mean cavernous tissue level for vancomycin was 55.5 +/- 5.5 ng./mg. (standard deviation) for 20 patients, while the mean cavernous tissue levels for aztreonam and gentamicin were 8.9 +/- 2.1 ng./mg. for 10 patients and 4.7 +/- 1.2 ng./mg. for 12 patients, respectively. When the delivery of antibiotic to cavernous tissue was compared (quantitated as ng. antibiotic per mg. tissue per mg. drug administered), a statistically significant value (p less than 0.01) was observed with vancomycin (0.11 ng./mg./mg.) greater than gentamicin (0.06 ng./mg./mg.) or aztreonam (0.01 ng./mg./mg.), and with no significant difference observed between aztreonam or gentamicin. These findings suggest that cavernous tissue levels may be used as a method to determine optimal antibiotic prophylaxis against penile prosthesis infection.

Aztreonam↗

PubMed1992

Rapid and sensitive assay for fluconazole which uses gas chromatography with electron capture detection.

Fluconazole, an orally active antifungal agent, has been shown to be clinically beneficial for maintenance therapy of cryptococcal meningitis. A sensitive gas-liquid chromatographic assay with electron capture detection, which required only a single extraction step and precluded any pretreatment of the chromatographic column, was developed for fluconazole. The assay was linear from 0.1 to 20 micrograms/ml, with a correlation coefficient of 0.999. The intraassay and interassay coefficients of variation were less than 9%. The measured values on average were within 8% of the target values. The extraction recoveries ranged from 87 to 106%. Steady-state plasma fluconazole levels (mean +/- standard deviation) in three AIDS patients with cryptococcal meningitis receiving 200 mg of fluconazole per day ranged from 8.95 +/- 1.32 to 11.41 +/- 0.63 micrograms/ml and were within the expected range for this dosing rate, on the basis of previous studies. The ratio of fluconazole concentration in cerebrospinal fluid to fluconazole concentration in plasma in one patient receiving 400 mg/day was 0.73 at steady state and was consistent with published reports.

Chromatography, Gas↗

PubMed1991

Treatment of abdominal malignant neoplasms using regional chemotherapy with hemofiltration.

The regional delivery of high-dose chemotherapy for malignant neoplasms of the limb with the isolated regional perfusion technique was first described in the late 1950s. Recently, the use of concomitant hemofiltration for rapid systemic drug removal permits the use of higher regional drug levels in treating patients with advanced abdominal malignant neoplasms without complete vascular isolation. Twenty-five patients successfully underwent 42 treatments of high-dose intra-arterial chemotherapy with concomitant hemofiltration at Tulane University Medical Center Hospital, New Orleans, La, from 1989 through 1990. One patient (4%) achieved a complete response. Two patients (8%) had partial responses following high-dose intra-arterial chemotherapy with concomitant hemofiltration and their residual disease was resected for cure. Seven patients (28%) achieved a partial response, 11 (44%) had stable disease, and four (16%) had progression of disease.

Abdominal Neoplasms↗

PubMed1991

Ciprofloxacin versus gentamicin in prophylaxis against bacteremia in transrectal prostate needle biopsy.

Consecutive patients with abnormal rectal examinations underwent transrectal needle prostate biopsy at VA Medical Center, New Orleans. Each patient was randomized to receive either gentamicin 1.5 mg/kg intravenously (IV) or 500 mg ciprofloxacin (Cipro-Miles) p.o., before and after the biopsy. Serum and prostate tissue levels of ciprofloxacin and gentamicin were measured by high-pressure liquid chromatography and by competitive binding immunoassay, respectively. Blood cultures were obtained, and the patients were observed for twenty-four hours after biopsy. After discharge the patients were followed up by telephone. The incidence of bacteremia and postbiopsy symptoms were less with ciprofloxacin. Prostate tissue levels of this drug were higher than gentamicin, while serum levels were roughly equivalent. Ciprofloxacin is less nephrotoxic, can be given orally, and has a better antimicrobial spectrum. We, therefore, recommend it as prophylaxis against bacteremia in transrectal prostate needle biopsy. Furthermore, it appears that prostatic drug levels are more important than serum levels in preventing bacteremia.

Aged↗

PubMed1991

Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus.

Single-dose and steady-state pharmacokinetics of the antiviral agent ribavirin were studied in seven male, asymptomatic, human immunodeficiency virus-seropositive subjects. After a single 400 mg intravenous infusion, mean terminal plasma half-life (t1/2) was 27.1 hours, mean volume of distribution was 802 L, and mean total plasma clearance was 26.1 L/hr. Renal clearance was 39% of total clearance and it exceeded creatinine clearance. Oral bioavailability was 44.6%. With long-term dosing (400 mg orally twice a day) ribavirin accumulated, reaching steady state in 2 to 4 weeks in plasma and red blood cells. Red blood cell concentrations greatly exceeded plasma concentrations (60:1). Plasma concentrations at steady state (trough) were 10- to 14-fold higher than the corresponding single-dose concentrations. The terminal t1/2 (washout) after 16 weeks greatly exceeded the t1/2 observed after a single oral dose (151 versus 29.6 hours). Ribavirin-induced reductions in hemoglobin ranging from 0.8 to 3.5 gm/dl were well tolerated. There was no significant reduction in CD4 lymphocytes during treatment with ribavirin for 16 weeks in subjects who had more than 200 CD4 cells at entry and who also remained free of opportunistic infections during 24 weeks of observation.

Administration, Oral↗

PubMed1991

Giant cell interstitial pneumonia.

Giant cell interstitial pneumonia is a distinctive and uncommon form of interstitial pneumonia. It is distinguished by the prominence of large, actively phagocytic alveolar giant cells of histiocytic origin in the presence of chronic interstitial pneumonia. Multinucleated type 2 granular pneumocytes are also identified. The multinucleated cells lack viral intranuclear inclusions of the type seen in measles pneumonia. Giant cell interstitial pneumonia may be idiopathic or it may occur with occupational exposure to hard metals or cobalt. We report this case to give recognition to an uncommon interstitial pneumonia.

Adult↗