Beth E Schilling

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A novel therapeutic compound was found to induce bladder tumors in male rats. Given the location of the tumors and the increased amounts of calcium- and magnesium-containing solids found in the urine of treated animals, we hypothesized that tumorigenesis was secondary to urine crystal formation rather than a direct effect of the drug on urothelium. To(More)
In carcinogenicity studies with PPAR gamma and alpha/gamma agonists, urinary bladder tumors have been reported in Harlan Sprague-Dawley (HSD) and Charles River Sprague-Dawley (SD) but not Wistar (WI) rats, with urolithiasis purported to be the inciting event. In two 3-month studies, the authors investigated strain-related differences in urine composition by(More)
Muraglitazar, a PPARalpha/gamma agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1%(More)
The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62(More)
The toxicity of muraglitazar, an oxybenzylglycine, nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in(More)
The toxicokinetic profile of D4T was assessed by conducting in vivo and in vitro studies. In the various studies, the i.v. and oral doses ranged from 12.5 to 600 and 5 to 2000 mg/kg, respectively. D4T was rapidly absorbed with an absolute oral bioavailability ranging from 77 to 100% in various species. The steady-state volume of distribution of D4T ranged(More)
The toxicokinetic profile of D4T was assessed by conducting in vivo and in vitro studies. In the various studies, the i.v. and oral doses ranged from 12.5 to 600 and 5 to 2000 mg/kg, respectively. D4T was rapidly absorbed with an absolute oral bioavailability ranging from 77 to 100% in various species. The steady-state volume of distribution of D4T ranged(More)
Rodent toxicology studies have historically been performed in wire-bottom cages, but the 1996 Guide for the Care and Use of Laboratory Animals recommends solid-bottom caging with bedding. Some investigators have expressed concern that changing to solid-bottom cages would interfere with technicians' ability to detect clinical signs. To test this hypothesis,(More)
Muraglitazar, a PPARalpha/gamma dual agonist, was dosed orally to rats once daily for 13 weeks to evaluate urinary and urothelial changes of potential relevance to urinary bladder tumorigenesis. Groups of 17 young or aged rats per sex were fed a normal or 1% NH4Cl-supplemented diet and were dosed with 0, 1, or 50 mg/kg muraglitazar. Lithogenic ions and(More)
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