Proliferative pituitary lesions in rats treated with salmon or porcine calcitonin.

Calcitonin, the serum calcium-lowering hormone, has been used in the treatment of hypercalcemia of malignancy and postmenopausal osteoporosis in humans for several years without any adverse effects. Recent studies in rats have indicated that calcitonin may be associated with morphologic effects on the pituitary. A large study was performed on 2 strains of rats, Sprague-Dawley (SD) and Fischer-344 (F-344), with 2 types of calcitonin, salmon-derived (sCT) and porcine-derived (pCT) calcitonin to evaluate possible effects on the pituitary. Sixteen groups of 42 male and 42 female SD or F-344 rats were given 0 (vehicle control), 1.25, 5.0, or 80.0 IU/kg/day of sCT or pCT, once daily, subcutaneously, for 1 yr. An increased incidence of adenomas of the adenohypophysis was observed in male SD rats at all dose levels of sCT, female SD rats given 80 IU/kg/day of sCT, male SD rats at the high dose level of pCT, and male F-344 rats at the high dose level of sCT. Also, an increased incidence of total proliferative lesions, due mostly to an increased incidence of focal hyperplasia of the pars distalis, occurred in female F-344 rats given the high dose of sCT. These pituitary proliferations were histologically similar to those that occur spontaneously, and the incidences observed were comparable to those that could occur in rats on 2-yr or lifetime studies, indicating that the injection of calcitonin had decreased the latency period.

Chronic toxicity/carcinogenesis study of temazepam in mice and rats.

The benzodiazepine temazepam was given to Charles River CD rats for 2 years in the diet at dosages of 10, 40, and 160 mg/kg day. An 18-month study was performed in Charles River CD-1 mice via dietary admixture at dosages of 10, 80, and 160 mg/kg/day. Mean body weights were significantly decreased for high dose rats of both sexes from Treatment Week 39 until termination. All drug treated male groups had a higher rate of mortality when compared to the male control groups, primarily due to deaths occurring between 19 to 24 months. Compound-related hepatic lipidosis accompanied by an increase in liver weights was observed at the high dose level in the 6- and 12-month and terminal sacrifices, as well as the middle dose level at the 12-month interim sacrifice. No evidence was found of compound induced carcinogenicity at any time period. Mortality for male mice was significantly higher in the two higher dose groups; this resulted from bite wounds associated with a drug-related increase in fighting behavior. An isolated finding of borderline statistical significance (p = 0.0556) was noted for hepatocellular adenomas in high dose female mice (4/100) at the 18-month terminal sacrifice. This incidence is well within the reported historical control range (0-14%). Minimal hepatoproliferative (hyperplastic nodules) and vascular effects (telangiectasis) were seen in the high dose male and female mice at the 18-month terminal sacrifice. Thus, these results were similar to those previously reported for oxazepam although meaningful effects on neoplasia did not occur with temazepam. Unlike in man, temazepam is primarily metabolized to oxazepam in the mouse and thus these results are not adverse with regard to human safety evaluation.

Toxicological evaluation of fluproquazone.

The toxicological characteristics of 4-(p-fluorophenyl-1-isopropyl-7-methyl-2-(1H)quinazolinone (fluproquazone), an analgesic with distinct antiinflammatory properties, were evaluated in acute and chronic toxicity studies as well as in reproduction toxicity, carcinogenicity and mutagenicity studies. The following overall results were obtained: The acute oral toxicity in mice, rats, and rabbits is of low order. In the chronic oral studies fluproquazone was generally well tolerated when given to rats and dogs for 13 weeks, to dogs and monkeys for 52 weeks, to mice for 78 weeks and to rats for 104 weeks. In particular, there was no indication of gastrointestinal irritations or lesions in any of these studies. The results of the studies in dogs and rats showed the major target organs for the toxicity of fluproquazone to be the liver and kidney, where mild, reversible changes were observed. These findings were considerably less severe than those found with several other antiphlogistic-analgesic compounds. In the reproduction toxicity studies, the only drug-related effects seen in experiments on female fertility or peri- and postnatal development in rats were a prolongation of pregnancy and an impairment of delivery leading to an increased perinatal mortality. These findings may be related to an inhibition of prostaglandin synthesis by fluproquazone. Similar effects are known to occur after administration of other inhibitors of prostaglandin synthesis. The oral teratological studies in rats and rabbits did not reveal any embryolethal or teratogenic effects. The drug had no mutagenic effects in either the micronucleus test and the dominant-lethal test using mice, or in the Ames-Test using Salmonella typhimurium. The carcinogenicity studies showed that fluproquazone has no carcinogenic potential in rats and mice.

The toxicology profile of the anti-inflammatory drug proquazone in animals.

Proquazone is a chemically distinctive non-steroidal anti-inflammatory drug (NSAID) and is orally effective as an anti-inflammatory, analgesic and anti-pyretic in animals. As with other NSAID's the main toxic effect was gastrointestinal irritation with sequellae. Comparative relative potency of proquazone with other NSAID's with regard to gastrointestinal effects was: rat-indomethacin greater than naproxen = proquazone greater than phenylbutazone; dog-indomethacin greater than naproxen greater than proquazone greater than phenylbutazone. In addition to gastrointestinal effects in minipigs, inflammatory renal changes occurred; renal changes also occurred in pigs treated with phenylbutazone. No evidence of carcinogenicity was seen in rodent oncogenicity studies. Evidence of teratogenicity was not seen in rat and rabbit teratological studies. In reproduction/perinatal studies in rats dose levels that induced intestinal lesions in the dams resulted in decreased survival of young to weaning. A major human metabolite of proquazone, the m-hydroxy derivative, was shown to be less toxic than the parent compound.