Biomedical subjects
W E Tucker
Publications and source records attributed to W E Tucker.
Nonclinical toxicology studies with zidovudine: acute, subacute, and chronic toxicity in rodents, dogs, and monkeys.
In single dose acute toxicity studies in CD-1 mice and CD rats, the median lethal dose (MLD) for zidovudine (ZDV) was > 750 mg/kg after iv dosing and > 3000 mg/kg after po administration (recommended human dose is 100 mg every 4 hr while awake). Because of the short half-life in rats (0.8 hr), dogs (1.0 hr), and monkeys (0.8 hr), the daily dose of ZDV in most studies was given in two equal portions approximately 6 hr apart. Intravenous administration of ZDV was well tolerated in beagle dogs at dose levels up to 42.5 mg/kg bid for 2 weeks and in CD rats at dose levels up to 75 mg/kg bid for 4 weeks. In a 2-week dose range-finding study in beagle dogs, cytostatic effects were noted at po dose levels of 62.5 to 250 mg/kg bid in certain tissues with rapid cell replication rates. In contrast, in 3- to 12-month oral toxicity studies in CD rats and cynomolgus monkeys, the principal toxicologic finding was reversible macrocytic normochromic anemia which occurred at 225-250 mg/kg bid in rats and 17.5-150 mg/kg bid in monkeys. In the 12-month rat study, RBC was decreased at 25 and 75 mg/kg bid. In the 12-month monkey study WBC was slightly decreased at 150 mg/kg bid.
Nonclinical toxicology studies with zidovudine: reproductive toxicity studies in rats and rabbits.
Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague-Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6-18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose, Cmax values in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a peri- and postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.
Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats.
Zidovudine (ZDV), an antiviral drug active in the treatment of acquired immunodeficiency syndrome (recommended human dose, 100 mg every 4 hr while awake), was evaluated for mutagenic and carcinogenic potential in a battery of short-term in vitro and in vivo assays and in lifetime studies in mice and rats. In L5178Y mouse lymphoma cells (tk+/- locus), a weak positive result was obtained only at the highest concentrations tested (4000 to 5000 micrograms/ml) in the absence of metabolic activation. In the presence of metabolic activation, the drug was weakly mutagenic at concentrations of 1000 micrograms/ml and higher. Following 24 hr treatment in the absence of metabolic activation, ZDV was moderately mutagenic at concentrations up to 600 micrograms/ml; dose-related structural chromosomal alterations were seen at concentrations of 3 micrograms/ml and higher in cultured human lymphocytes. Such effects were not noted at the two lowest concentrations tested, 0.3 and 1 microgram/ml, and BALB/c-3T3 cells were transformed at concentrations of 0.5 microgram/ml and higher. No effects were seen in the Ames Salmonella plate incorporation and preincubation modification assays (possibly due to bacteriocidal activity of ZDV at low concentrations) at concentrations ranging from 0.01 to 10 micrograms/plate or in a single-dose intravenous bone marrow cytogenetic assay in CD rats. In multidose micronucleus studies, increases in micronucleated erythrocytes were seen in mice at doses of 100 to 1000 mg/kg/day. Similar results were seen in rats and mice after 4 or 7 days of dosing at 500 mg/kg/day. In carcinogenicity bioassays, adjusted doses of 20, 30, or 40 mg/kg/day and 80, 220, and 300 mg/kg/day were given to CD-1 mice and CD rats, respectively, for up to 22 months in mice and 24 months in rats. ZDV caused a macrocytic, normochromic anemia in both species. No evidence of carcinogenicity was seen in male mice or rats. In female mice, five malignant and two benign vaginal epithelial neoplasms occurred in animals given 40 mg/kg/day. A single benign vaginal epithelial tumor was seen in a mouse given 30 mg/kg/day. In rats, two malignant vaginal epithelial neoplasms were seen in animals given 300 mg/kg/day. In a 7-day study in mice, ZDV was shown to be devoid of estrogenic activity. In an oral pharmacokinetics study, the AUC was 17 and 140 micrograms/ml.hr in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. In contrast, the average steady-state concentration in humans at the recommended daily dose is 0.62 microgram/ml. Twenty-four hour urine concentrations were 1245 and 4417 micrograms/ml in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. These values were approximately 26- and 136-fold higher than the human urine concentration at the recommended daily dose. In a one- to three-day study with intravenously administered sodium fluoroscein in rats and mice, retrograde flow of urine into the vagina was demonstrated. In a subsequent lifetime carcinogenicity bioassay in mice in which ZDV was given intravaginally at concentrations of 5 or 20 mg ZDV/ml in saline, 13 vaginal squamous cell carcinomas were seen at the highest concentration tested. It was concluded that the vaginal tumors seen in the oral carcinogenicity studies were the result of chronic local exposure of the vaginal epithelium to high urine concentrations of ZDV.
Radiological case of the month. Dermoid cyst.
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Neurotoxic effects of the anti-varicella zoster virus agent 2'-valeryl-6-methoxypurine arabinoside in monkeys and rats dosed orally for 90 days.
The 2'-valerate ester of 6-methoxypurine arabinoside (170U88), a nucleoside analog with anti-varicella zoster virus (VZV) activity, was given to monkeys and rats. In subchronic preclinical toxicity studies, dosing was by gavage to monkeys (distilled water vehicle) and rats (0.5% methylcellulose vehicle) for 90 days. Groups of 5 male and 5 female monkeys (Macaca fascicularis) were given 170U88 at 0, 25, 50, or 100 mg/kg/day. The daily dose was given in two equal portions with 6 hr between doses. Monkeys in the high-dose group lost weight. Food consumption was decreased for mid- and high-dose monkeys and for low-dose female monkeys. Slightly decreased values for erythrocyte and leukocyte counts at the mid- and high dose were fully reversed during an 8-week recovery period. Two high-dose male monkeys and a middose female monkey developed signs of central nervous system toxicity and were necropsied before dosing was complete. These signs were first observed in the fifth week of dosing and included body tremors, incoordination, reduced activity, sleepiness, stupor, and lack of eye tracking. Axonal lesions were observed in histologic sections of sciatic nerve in monkeys at all dose levels. Neither the signs of central nervous system toxicity nor the axonal lesions reversed during the 8-week recovery period. Groups of 14 male and 14 female CD rats (Sprague-Dawley derived) were given single daily doses of 170U88 at 0, 150, 300, or 600 mg/kg. Body weights were decreased at all dose levels and food consumption was decreased for mid- and high-dose rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Postnatal survival in Wistar rats following oral dosage with zidovudine on gestation day 10.
Groups of 20 female Wistar rats from Charles River Breeding Laboratories (Kingston, NY) were given three oral doses of 100 mg zidovudine/kg at 5-hr intervals on Gestation Day 10 (total dose = 300 mg/kg). Control rats received three oral doses of the vehicle, distilled water. This design approximated that of an earlier study that reported 38% postnatal mortality among the offspring of Wistar rats given zidovudine. In the study reported here, no adverse effects were noted on maternal body weight, food consumption, reproductive capacity, or hematology. Similarly, no effects on growth or survival of the offspring were noted. Hematology and clinical chemistry values were comparable between offspring of treated and control dams, and no treatment-related gross or histopathologic lesions were noted in the weanling rats. The mean concentration of zidovudine in embryonal homogenates, collected 30 min after administration of the third dose to the dam on Gestation Day 10, was 21.1 micrograms/g tissue. This value is approximately one-third of the mean drug plasma concentration (62.6 micrograms/ml) measured in the dams at the same time point. The dramatic difference in results in the two studies may be related to differences in Wistar rats from two different sources or to other unknown factors associated with the design and conduct of the studies. The results of the current study were consistent with other preclinical studies on the reproductive toxicity of zidovudine in rats and rabbits.
Transsphincteric approach to lesions of the rectum.
Transsphincteric posterior resection of villous adenomas and small carcinomas restored gastrointestinal continuity and preserved continence in 25 of 26 patients in this study. No patient had local recurrence. This procedure is suitable for villous tumors that are too high for transanal or too low for transabdominal resection, and for small mobile malignancies of the lower 5 cm of the rectum.
Nail loss and footpad erosions in beagle dogs given BW 134U, a nucleoside analog.
The oral administration of BW 134U to Beagle dogs in a 1-month study was associated with lameness, footpad erosions, and nail loss. Groups of dogs received 60, 120, and 240 mg/kg/day. Compound-related effects were observed in the high dose group and only during the postdose period. Light microscopy revealed prominent cell maturation or radiomimetic defects in the stratum germinativum of the distal phalanges and footpads. The mechanism by which BW 134U produced these cell maturation defects is unknown. There were no signs of adverse effects in other keratin-producing or keratin-containing tissues.
Dose selection as it pertains to testing a prodrug in carcinogenicity bioassays.
Toxicologists need more information than is usually available in the early stages of development of a drug in order to choose proper dose levels for testing in the bioassays. The approach most likely to result in successful bioassays involves an early multidisciplinary effort in which there is pharmacokinetic characterization of the test material in both rats and mice. Preliminary 3 month studies are desirable. Periodic sampling of plasma is essential to detect possible non-linear kinetics (as in the example we report herein) reflected as accumulation of the test material or metabolites. This is true regardless of the test substance. However, if one tests prodrugs it may be particularly helpful to know if chemical or enzymatic conversion of the prodrug is linear and if there is reversion to prodrug or other abberant metabolism. Failure to rule out these possibilities could result in subsequent clinically irrelevant organ damage or could compromise longevity or the interpretation of results in lifetime studies. Pharmacokinetic considerations are as valid as the more traditional biologic or morphologic end points used to estimate maximum tolerated or no-effect dose levels.
Preclinical toxicology of bupropion: an overview.
In preclinical studies, the toxicologic profile of bupropion was determined in laboratory animals using exaggerated doses of drug in a variety of toxicologic assays. Under overdose conditions, clinical signs primarily referable to the central nervous system were seen in rats, mice, rabbits, and dogs. Very mild, reversible hepatotoxicity and anemia occurred in dogs with chronic dosing; lifetime administration in rats caused hepatocellular hypertrophy and focal hepatic hyperplasia. In both rats and dogs, there was an increase in liver weight related to hepatic enzyme induction. Appropriate tests indicated that bupropion is unlikely to have the potential to cause teratogenic, mutagenic, or carcinogenic effects in man.
Preclinical toxicology profile of acyclovir: an overview.
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The effect of dopamine on postburn myocardial depression.
Myocardial performance is severely depressed following burns to more than 30% of the body surface area. Cardiac output in the immediate postburn period is dissociated from plasma volume. Many attempts have been made to improve early postburn hemodynamics with little success. Continuous infusion dopamine in low doses has recently been reported to improve at least one index of cardiac performance (LVSWI). We report the use of low-dose (5-10 mcg/kg X min) dopamine in the first 24 hours postburn in 20 seriously burned adults. Hemodynamic data are presented immediately preinfusion and after 1 hour of dopamine. Low-dose dopamine produced no change in cardiac index, arterial pressure, LVSWI, or any other hemodynamic parameter. We conclude that dopamine is of no benefit in treating the depressed myocardial function seen following major burns.
Evaluating the rat inner ear. A technique using scanning electron microscopy.
The laboratory rat is the most commonly used species in safety evaluation of pharmaceutical compounds. However, surface preparations of the organ of Corti (OC) are difficult to perform in this species largely due to problems in removing the thick, bony otic capsule. A modified technique was developed using rapid decalcification to solve this problem. In addition, scanning electron microscopy was used to quantitate hair cell damage and/or loss after exposure of the OC by microdissection. It was found that hair cell loss and amage could be easily detected and quantified in rats given gentamicin sulfate.
Infected prosthetic grafts.
An experience with 20 infected prosthetic grafts in a series of 652 prosthetic arterial reconstructions has been reviewed. There was 13 aortofemoral, one straight aortic, three femoropopliteal, one carotid subclavian, one axilloaxillary, and an axillocarotid graft. The most common site of infection was the groin. All patients had received preoperative and postoperative broad-spectrum antibiotic coverage, perhaps contributing to a high incidence of Gram-negative bacterial cultures. Early procrastination contributed to morbidity and mortality. Attempts at local wound management with drainage and irrigation generally failed, especially if the suture line was involved. Graft excision without revascularization resulted in a number of amputations and a high mortality. Excision of the entire aortofemoral graft combined with extra-anatomical revascularization was uniformly fatal. Our experience suggests that the first objective should be to establish operatively the extent of the infection. If very localized, antibiotic irrigation may cure. Involvement of one side can be treated in one stage by extra-anatomical bypass using the obturator foramen coupled with excision of the infected portion. If the entire graft is involved, we recommend extra-anatomical bypass as the initial procedure. High-dose antibiotic for systemic effect are then administered and two to three days later the infected graft is removed.
Postoperative necrotizing fasciitis of the abdominal wall.
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Treatment of experimental herpes simplex keratitis with acycloguanosine.
Acycloguanosine, a recently developed compound with high inhibitory activity against viruses belonging to the herpes group, has been evaluated in experimental herpes simplex keratitis in rabbits in comparison with trifluorothymidine and preparations of idoxuridine and vidarabine at present in clinical use. All compunds were used in the form of ophthalmic ointments which were applied 5 times a day at intervals of 2 hours. Treatment began on the third day of infection and was continued for 4 days. Complete cure was obtained with acycloguanosine and idoxurdine; trifluorothymidine and vidarabine were considerably less effective. Acycloguanosine was equally effective when given intravenously in the form of its sodium salt, and could be detected in the tear fluid in inhibitory concentrations when given by mouth. The compound was relatively free from toxicity.
Sex- and species-related nephropathy of 6-(1-aminocyclohexanecarboxamido)penicillanic acid (cyclacillin) and its relationship to the metabolic disposition of the drug.
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