Toxicological evaluation of substituted dicyclopentadienyliron (ferrocene) compounds.

The acute toxicity of 3 substituted ferrocenes: acetylferrocene, ethylferrocene, and 2,2-bis(ethylferrocenyl)propane (Catocene) were studied in rats, rabbits and monkeys. Acetylferrocene was found to be the most toxic. The oral lethal dose was less than 5 mg/kg for female rats, between 5 and 50 mg/kg for male rats, and between 10 and 100 mg/kg for monkeys. The toxicity of acetylferrocene appeared to be delayed, with most mortality occurring on the third day after dosing. Acetylferrocene was also highly toxic by skin or eye exposure. Gross pathological examination revealed signs of pneumonopathy in both the rats and monkeys. The mechanism by which monkeys are less susceptible than rats to the toxicity of acetylferrocene is not clear.

The analgesic and anti-inflammatory profile of ketorolac and its tromethamine salt.

Ketorolac tromethamine[(+/-)-5(benzoyl)-2,3-dihydro-1N-pyrrolizine-1-carboxylic acid tris hydroxymethylaminomethane salt] is a highly potent member of a new class of compounds having analgesic and anti-inflammatory activity. When given orally in tests involving underlying inflammation it was a potent analgesic, whereas it was inactive in tests for narcotic activity. It was also highly active orally in rat models of acute and chronic inflammation and pyresis. These properties are mediated primarily via the compound's potent prostaglandin cyclooxygenase inhibitory activity. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity. A single 10 mg tablet given orally to human volunteers following surgery provided pain relief equivalent to that provided by 10 mg of morphine given intramuscularly. When given intramuscularly to rabbits (0.25 ml of a 0.31-5% solution) or man (3 ml of a 1-3% solution), no drug-related irritation or changes in creatine phosphokinase were seen. Solutions (less than or equal to 0.5%) applied to the eyes of animals and man were not irritating. When applied topically in rat and rabbit models of ocular inflammation, less than or equal to 0.5% solutions of ketorolac tromethamine inhibited the inflammatory response.

Induction of constant sensitivity to dinitrochlorobenzene in the cynomolgus monkey.

A technique for the induction of contact sensitivity in the cynomolgus monkey is described. Seventy percent of the monkeys gave a positive reaction when skin-tested 18 days after sensitization with dinitrochlorobenzene. When re-tested on day 27, both the number of reactors and the intensity of the reactions had increased. Histological examinations showed perivascular leukocytic infiltration with an increased proportion of mononuclear cells, typical of a delayed hypersensitive reaction.

Mammary nodular hyperplasia in intact rhesus monkeys.

PIP: Clinical and pathological findings of subcutaneous nodules in the breast regions of 2 untreated control intact female Rhesus monkeys in a long-term study of an oral contraceptive steroid are described. 1 nodule, which was excised early in the study, showed changes characteristic of nodular mammary hyperplasia; no features of neoplasia were present. Some of the nodules were transient. None of the nodules showed a progressive growth pattern during repeated clinical examination over 17-20 months.^ieng