Subchronic urinary bladder effects of muraglitazar in male rats.

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 sediment were profiled from freshly voided urine samples collected 24 h after dosing, and drug exposures were measured. Urinary citrate, oxalate, and epidermal growth factor (EGF) were assayed from 18-h urine collections. Urothelium was assessed by light microscopy, scanning electron microscopy, and BrdU and TUNEL immunohistochemistry. When fed a normal diet, urine pH was higher in males (above 6.5). Urine volume/body weight was greater in females. Urine soluble/total calcium and magnesium and phosphorus/creatinine ratios were lower in male rats fed a normal diet. Urine citrate levels were decreased and oxalate was increased in young male rats treated with 50 mg/kg muraglitazar compared to age/sex/diet-matched controls. No changes in urine sediment were detected 24 h after dosing. In young male rats treated with 50 mg/kg on normal diet, multifocal urothelial necrosis and proliferation were observed, whereas urothelial apoptosis and urine EGF levels were unchanged compared to age/sex/diet-matched controls. Urothelial necrosis and proliferation were not correlated to systemic or urinary drug exposures and were prevented by dietary acidification. These data suggest that muraglitazar-associated changes in urine composition predispose to urothelial cytotoxicity and proliferation in the urinary bladder of young male rats and that urine sediment must be profiled at multiple daily timepoints to fully qualify drug-induced changes in urine composition.

Hepatic gene expression and lipid homeostasis in C57BL/6 mice exposed to hydrazine or acetylhydrazine.

Hydrazine (HD) and acetylhydrazine (AcHD) are metabolites of the antituberculosis drug isoniazid (INH) that have been implicated in INH-induced liver damage. The hepatotoxicity of AcHD and HD were compared in adult male C57Bl/6J mice by evaluating hepatic histopathology, plasma biochemistry, and hepatic gene expression. By all measures, HD had significantly greater effects than AcHD. There was no evidence of liver damage following exposure to AcHD (300 mg/kg, po). However, HD at this dose caused marked hepatic necrosis, macrovesicular degeneration, and steatosis. Lipid accumulation was initiated 2 h after HD exposure, with hepatic macrovesicular degeneration evident after 4 h, and severe necrosis by 36 h. Gene expression profiles were compared 24 h following 100 mg/kg po of HD or AcHD. HD changed the hepatic expression of more genes than AcHD, particularly lipid synthesis, transport, and metabolism genes that may be involved in steatosis. Hepatic expression of genes regulated by peroxisome proliferator activated receptors (PPAR) and sterol regulatory element binding protein (SREBP) transcription factors was increased only by HD. The hepatotoxicty and hepatic gene expression profile of HD, but not AcHD, indicate that exposure to HD initiates a process whereby the production and intracellular transport of hepatic lipids is favored over the removal of fatty acids and their metabolites.

Effects of extracorporeal shock wave therapy on bone.

Extracorporeal shock waves have been used for 30 years to fragment uroliths for nonsurgical treatment for urolithiasis in humans. Applied to bone, shock waves delivered at the appropriate energy and pulse number, can stimulate osteogenesis. In Europe, shock waves are routinely used to treat nonunions in humans despite poor understanding of the mechanism of action. Shock wave therapy has also been used clinically in horses. Preliminary experimental studies indicate that shock wave therapy does not damage soft tissue in the distal aspect of the equine limb and can stimulate osteogenesis throughout the depth of the near cortex of the metacarpus and metatarsus.