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Three separate control lifetime studies were conducted with untreated Crl:CD-1 (ICR)BR mice using a total of 400 mice/sex maintained to 21 mo of age. Similar husbandry practices and environmental conditions were used for all 3 studies. It was noted after study initiation that the Charles River breeding facility of origin was different for each study. The aggregate range of survival and incidence of neoplasms for the combined studies was similar to that previously reported. However, these 3 groups of mice had prominent variation in survival and in the incidence of pulmonary adenomas and systemic amyloidosis in males and females, and in the incidence of hepatocellular neoplasms in males. The present studies indicate that consistent procurement of test animals is an additional variable to be considered in the establishment of a valid database within a test facility when using an outbred mouse.

The antidepressant drug fluoxetine HCl was tested for carcinogenicity in three well designed and controlled studies in Fischer rats and C57BL/6 x C3H F1 mice. The compound was administered to the animals for 24 months at dietary doses of approximately 0, 0.5, 2.0, or 10.0 mg/kg body weight in rats and 1.0, 5.0, or 10.0 mg/kg in mice. The highest dose tested was a maximum tolerated dose for both species as evidenced by clinical signs (rats and mice) and some mortality (mice) referable to central nervous system pharmacological effects, decreased weight gain (rats), and histopathological changes of phospholipidosis (rats) and hepatic fatty change (mice). There was no evidence of an increased incidence of any type of unusual or commonly occurring spontaneous neoplasm in either rats or mice. There were statistically significant decreases in a few commonly occurring neoplasms. The data reported herein provide convincing evidence that fluoxetine is neither a complete carcinogen nor a tumor promoter.

The nephrotoxic potential of four oral cephalosporin antibiotics, cephalexin, cefaclor, LY195885 and LY171217, was determined in rabbits given single oral doses of 250-500 mg/kg body weight. Histopathological changes, blood chemistry, and ex vivo renal slice function were evaluated 48 hr after dosing. Additionally, the viability of rabbit renal cells in culture (LLC-RK(1)) was evaluated by nigrosin dye exclusion after 48 hr exposure to each antibiotic at concentrations of 0.5-2.0 mg/ml. Only LY171217 was significantly nephrotoxic in vivo. Prominent lesions were observed at 500 mg/kg body weight and were accompanied by marked increases in blood urea nitrogen and serum creatinine, and decreases in ex vivo renal slice gluconeogenesis and p-aminohippurate and tetraethylammonium uptake. In vitro toxicity to renal cells correlated well with the in vivo results yielding TC(50) values (TC(50) = concentration producing 50% lethality) > 1.0 mg/ml for cephalexin, LY195885 and cefaclor. LY171217, on the other hand, was significantly toxic in vitro (TC(50) = < 0.5). These results suggest that renal cells in culture may provide a useful method for examining the nephrotoxic potential of oral cephalosporins before in vivo studies.

Data from 1858 mice at Lilly and eight studies from the literature were used to establish a negative correlation between proliferative hepatic lesions and malignant lymphoma in rodents. This negative correlation implies that the rodent model is flawed in the sense that interpretation of hepatic lesions without consideration of malignant lymphoma can lead to the incorrect conclusion that there is something unique about the compound. In fact it is the rodent model that has a unique feature--the negative correlation.

The serum levels of two enkephalins after various routes of administration were compared in rats. The results indicated that serum levels of metkephamid after nasal administration were not significantly different than levels after intravenous injection. The oral administration of metkephamid resulted in undetectable serum levels. The effects of a promoter and variations in the peptide dose on nasal absorption were studied. Depending on the stability of the polypeptide and its susceptibility to enzymatic degradation, nasal absorption of peptides can be influenced by the presence of a promoting agent in the formulation. A linear relationship between the dose and the AUC was observed in the range of concentrations studied. The absorption mechanism appears to be passive diffusion. Microscopic examinations of nasal mucosa in rats revealed degrees of irritation which, considering the experimental exposure, were slight and probably repairable. The data indicate that enkephalins can be absorbed through the nasal mucosa into the systemic circulation, and the onset of absorption was rapid. Nasal administration may offer an attractive alternative for the delivery of proteins and/or polypeptides which are, in general, absorbed poorly when given orally.

Attempts to define the etiology of abortions on a regular continuing basis have been few, and largely unsuccessful. Problems of such a project include cost, difficulty of securing satisfactory samples, a laboratory organization of sufficient breadth, capacity and dedication to perform and interpret the necessary examinations, knowledgeable cooperation of the practitioner, and past reliance on isolated findings substituting for sound criteria for diagnosis. A program was created which was intended to overcome the difficulties. The plan was so constructed as to permit addition or removal of procedures as indicated.

The blood levels of the [14C]clofilium ion in rats after various routes of administration of clofilium tosylate were compared. The results indicate that the blood levels after nasal administration were not statistically different from levels after intravenous administration (p greater than 0.05). Administration by the oral route resulted in considerably lower blood levels. Nasal administration of clofilium tosylate appeared to be superior to oral administration. Histological examinations of nasal mucosa were conducted. At the lower concentration, mild necrosis was observed, and large areas of mucosa were unaffected. However, necrosis of large areas of mucosa occurred after exposure to the higher concentration. Levels of radioactivity in heart, liver, lung, and kidney tissue, as a function of time, were also studied. Unlike the blood levels after nasal administration, the levels of radioactivity were persistent in heart tissue. The data suggest that the [14C]clofilium ion and/or metabolite concentrate in the heart and that blood levels of radioactivity may not be an accurate index of cardiac levels or biological response.