No abstract

ABSTRAC~Data from 500 male and 500 female Sprague-Dawley rats used as controls in studies performed at Huntingdon Research Centre to assess the safety of drugs were sampled at 17, 30, 56, 82, or 108 weeks of age. Plasma urea nitrogen levels remained constant, except in aged males. Aging caused increased proteinuria and decreased urinary concentrating ability, in addition to increased size, weight, and degree of cortical scarring of kidneys. Chronic progressive nephropathy, first seen histopathologically at 30 weeks of age, accounted for these changes and ultimately affected 81% of male and 44% of female rats. One-fifth of twoyear-old male rats had diffuse parenchymal damage and a small number also had secondary hyperparathyroidism. Other notable changes included basophilic (often colloid-filled) cortical tubules, mononuclear cell infiltrations, parenchymal and pelvic mineralization, urothelial hyperplasia, and pyelonephritis. Miscellaneous low incidence findings included one lipomatous tumour and generalized lymphosarcoma. INTRODUC~IONDrug safety assessment depends on distinguishing spontaneous changes and pharmacological responses from toxic reactions. Base-line data are useful for putting anomalies into perspective and interpreting results (22). Age-related renal functional changes and lesions of rats have been reviewed several times (3, 8, 10, 14,28). Chronic progressive nephropathy (3) is of major importance in some strains of laboratory rats, and Sprague-Dawley rats are apparently more prone to develop this condition than are Wistars (30). This paper reports a retrospective survey of data obtained from a large number of laboratory-maintained Sprague-Dawley rats. METHODSData for this survey originated from records of chronic toxicity studies undertaken with SpragueDawley rats (CD strain from Charles River, Manston, UK, Wilmington, USA or St. Aubin-Les-Elbeuf, France) at the Huntingdon Research Centre between 1968 and 1979. Details of the rats used as untreated controls were examined. The rats were barrier maintained and housed in groups of five in suspended metal cages that had wire mesh floors. Room temperature and relative humidity were maintained at 21°C f 2°C and 50% 4 5% respectively. Lighting was controlled to allow 12 hours light (0800 to 2000 hours) and 12 hours dark per day. Except when blood or urine samples were taken, rats received Spillers' Laboratory Small Animal Diet or Spratts' Laboratory Rodent Diet Nos. 1 or 2 and tap water adlibition. Food was withheld overnight prior to obtaining blood from the orbital sinus of rats anesthetised with ether. Water was withdrawn when individual 16-1 8-hour overnight urine samples were obtained from rats placed in metabolism cages fitted with faecal separators. Blood samples were analyzed for plasma urea by routine methods. The volume of overnight urine voided was measured and the pH, specific gravity, and protein concentration were determined. At the end of the experimental periods, the rats were killed by carbon dioxide asphyxiation. A full macroscopic pos...

No abstract

The carbonic anhydrase inhibitors, acetazolamide and MK-0927, were given by oral route to male SpragueDawley rats at 200 mg/kg/day and 25 mg/kg/day, respectively, for up to 4 weeks. Sequential necropsies were performed and urinary bladders were examined by light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Similar urinary bladder changes were seen with both compounds. SEM evidenced slight multifocal urothelial changes consisting of cell swelling, dissociation, degeneration, and exfoliation after 3 and 5 days of treatment. After 2 and 4 weeks of treatment, elevated or leafy microridges on the luminal cell surfaces were seen together with foci of swollen cells. After a 2-monthrecovery-period, the urothelial surfaces were normal. LM and TEM showed multifocal vacuolation of the urothelium associated with inflammation of the underlying lamina propria after 3 and 5 days of treatment. Cellular hypertrophy and hyperplasia of the transitional epithelium was seen after a 5-day treatment, persisted without increasing severity after 2 and 4 weeks of treatment, and totally regressed after the recovery period. It was concluded that, in the rat urinary bladder, oral administration of acetazolamide and MK-0927 induced early degeneration and inflammation followed by epithelial regeneration, resulting in a reversible hyperplasia of the transitional epithelium.

No abstract

Single doses of aspirin induce scattered foci of necrosis of proximal tubules in some strains of rats, whereas acute or sub-acute administration of phenylbutazone causes renal papillary necrosis. Initially, using Sprague-Dawley rats of CFY and CD strains, it became clear that these rats were not as susceptible to these drugs as the literature suggested. Aspirin-induced necrosis was apparently sex-related, being seen in females but could be induced by hormone treatment in males. Male Wistar and Sprague-Dawley rats had reacted differently to administration of phenylbutazone for two weeks. Two experiments were performed with four rat strains: Wistar, Lister-Hooded, Sprague-Dawley, and Fischer-344. The rats were six weeks old at the start of the experiments. Five males and five females of each strain were gavaged with either a single dose of 1,000 mg/kg of aspirin or 200 mg/kg phenylbutazone once daily for four weeks. The drugs were suspended in methylcellulose, which was given to equal numbers of control male and female rats in each experiment. The rats were maintained under standard conditions. Blood and 18-hour overnight urine samples were collected prior to sacrifice. There were no strain-related differences in the types of renal lesions seen, however there were differences in the degrees of responses to the two drugs. With aspirin the female Fischer-344 rats were the most susceptible showing necrosis of proximal tubules of both kidneys and markedly elevated urinary protein concentration and gamma-GT activity. Other females showed less change. Male rats were affected only slightly and males of the Wistar strain were not.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

No abstract