Christian L. Gries

Exploration of the Negative Correlation between Proliferative Hepatocellular Lesions and Lymphoma in Rats and Mice—Establishment and Implications

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.

Positive Correlation of Body Weight with Pituitary Tumor Incidence in Rats

Data based on 4700 Wistar rats in 13 two-year studies were used to calculate the correlation between body weight at 12 months and pituitary tumor incidence. The positive correlations of 0.754 for male rats and 0.828 for female rats were both highly significant (p less than 0.0001). The results indicate that any treatment which causes increased body weight will probably be associated with an increased incidence of pituitary tumors.

Adenoma and Carcinoma, Pars Distalis, Rat

Pituitary neoplasms vary greatly in size, from single or multiple microscopic foci to large masses that replace the whole gland, markedly enlarging it up to a diameter of 20 mm and a weight of 350 mg or more (Kovacs et al. 1977; Fig. 125). The tumors are generally well defined, spherical, circumscribed, soft, friable, and smooth, but they may have an irregular nodular surface and they are not encapsulated. Either they are solid, or they contain cavernous vessels with hemorrhages and congestion (Andersson 1969). The tumors are separated from the brain, but a few tumors invade the adjacent brain and meninges. Large tumors protrude from the sella and produce compression atrophy of the adjacent brain parenchyma (Wolfe et al. 1938; Ross et al. 1970; Kovacs et al. 1977). The cut surface is light brown to dark red depending on the vascularity of the neoplasm.

Pituicytoma, Neurohypophysis, Rat

This neoplasm of the pars nervosa is solid, relatively firm, and causes enlargement of the pituitary gland and compression atrophy of the overlying hypothalamus. Its size may vary from microscopic dimensions to several millimeters in diameter.

Developmental Toxicology Studies of Vancomycin Hydrochloride Administered Intravenously to Rats and Rabbits

Pregnant CD rats were given vancomycin intravenously in doses of 0, 40, 120, or 200 mg/kg on Gestation Days (GD) 6-15; pregnant New Zealand white rabbits were given 0, 40, 80, or 120 mg/kg intravenously on GD 6-18. Cesarean sections were performed on rats and rabbits on GD 20 and 28, respectively. In rats, maternal toxicity was indicated in the 120- and 200-mg/kg treatment groups by cortical tubular nephrosis. Maternal body weight gain and food consumption and fetal viability, weight, and morphology were not adversely affected by vancomycin. Maternal and developmental no observed adverse effect levels (NOAELs) in the rat were 40 and 200 mg/kg, respectively. In rabbits, maternal toxicity was indicated by cortical tubular nephrosis in the 80- and 120-mg/kg treatment groups; a single death and depression of body weight gain and food consumption occurred in the 120-mg/kg treatment group. Developmental toxicity was indicated by depression of fetal weight in the 120-mg/kg treatment group; fetal viability and morphology were not adversely affected by vancomycin. Maternal and developmental NOAELs in the rabbit were 40 and 80 mg/kg, respectively. Based on these data, vancomycin did not exhibit selective toxicity toward the developing rat or rabbit conceptus.

Adenoma and Carcinoma, Pars Distalis, Anterior Pituitary Gland, Rat

Pituitary neoplasms vary greatly in size, from single or multiple microscopic foci to large masses that replace the whole gland, markedly enlarging it up to a diameter of 20 mm and a weight of 350 mg or more (Kovacs et al. 1977b; Fig. 83). The neoplasms are generally well defined, spherical, circumscribed, soft, friable, and smooth, but they may have an irregular nodular surface, and they are not encapsulated. Either they are solid, or they contain cavernous vessels with hemorrhages and congestion (Andersson 1969). The neoplasms are separated from the brain, but a few invade the adjacent brain and meninges. Large neoplasms protrude from the sella and produce compression atrophy of the adjacent brain parenchyma (Wolfe et al. 1938; Ross et al. 1970; Kovacs et al. 1977b). The cut surface is light brown to dark red depending on the vascularity of the neoplasm.

Nasal Absorption of Enkephalins in Rats

In recent years, the possibility that the intranasal administration route might be useful for many compounds which are not absorbed orally has received a great deal of attention. For instance, the β-blocker propranolol (Hussain et al, 1979, 1980 a, b), the contraceptive agent progesterone (David et al, 1981; Hussain et al, 1981) and the anti-arrhythmic compound clofilium tosylate (Su et al, 1984) have been shown to be effectively absorbed via the intranasal route when compared to oral administration. These compounds undergo extensive degradation due to first-pass hepatic metabolism which can be minimized after nasal administration. For drugs which are poorly absorbed by the oral route such as sulbenicillin, cefazolin, and cephacetrile, it was demonstrated that the percent dose excreted in urine after nasal administration was nearly one-half of that after intramuscular administration (Hirai et al, 1981). The absorption of low molecular weight polypeptides, luteinising hormone-releasing hormone (LH-RH) and its analogues used as a contraceptive agent, was evaluated by the nasal route (Fink et al, 1974; Berquist et al, 1979; Gennser and Liedholm, 1974; London et al, 1973; Anik et al, 1984). Although the absorption efficiency by the nasal route was lower than the I.V. route for these polypeptides, the absorption was reproducible, and the advantage of non-parenteral route for such a compound was an important factor. Research has also been carried out on the nasal absorption of high molecular weight polypeptides such as insulin (Moses et al, 1983; Hirai et al, 1978, 1981 a,b), interferon (Greenberg et al, 1978; Harmon et al, 1976; 1977; Johnson et al, 1976) and growth hormone releasing factor (Evans et al, 1983).

Cysts, Pituitary; Rat, Mouse, and Hamster

Cysts of the craniopharyngeal duct in rodents are usually microscopic. A few large cysts enlarge the gland and may appear as blisterlike lesions filled with mucoid-colloid material.

Inflammation, Pituitary Gland: Rat, Mouse, and Hamster

Inflammatory cell infiltrations of the pituitary gland, by extension from the meninges, usually produce no gross alterations; pituitary gland involvement in these cases is detected by histopathologic examination. Severe, suppurative inflammation leading to abscess formation may produce enlargement and distortion of the gland, however.

Adenoma, Pars Intermedia, Anterior Pituitary, Rat

Adenomas of the pars intermedia of the pituitary gland (as defined by the WHO*/IARC international classification of rodent tumors) vary in size and may cause enlargement of the gland. The gross appearance is similar to the solid chromophobe adenoma of the pars distalis.