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Ketorolac tromethamine is a highly potent member of a class of compounds having both analgesic and antiinflammatory activity. In animal pain models using underlying inflammation, ketorolac markedly inhibited the pain response and increased the pain threshold; it did not exhibit any narcotic or central nervous system depressant effects. It was also active in rat models of acute and chronic inflammation and pyresis. These activities are mediated primarily by potent prostaglandin cyclooxygenase inhibitory activity. Mild central nervous system and cardiovascular effects occurred only at doses far greater than those required for analgesic and antiinflammatory activity. Solutions of ketorolac tromethamine are not irritating. When given intramuscularly to rabbits (0.31-5% solutions), no drug-related irritation or changes in serum creatine phosphokinase were seen. The agent was not irritating when applied to the skin or eyes (less than or equal to 0.5% solutions) of animals.

The Freund's adjuvant-injected rat shares a number of features with the arthritis patient, viz the presence of a proliferative synovitis, joint swelling, and cartilage and bone erosion. Naproxen, a prostaglandin synthetase inhibitor which is an effective antiinflammatory agent in laboratory animals and humans, was evaluated as an inhibitor of connective tissue destruction in this model by use of radiologic and histopathologic analyses. Sixteen days after rats were injected with Freund's complete adjuvant, marked joint swelling was noted. On day 17, vehicle or naproxen, 7 mg/kg/day, was administered orally. Twenty-eight days later vehicle-treated animals demonstrated the following pathologic changes in their hindpaws; swelling, cartilage loss, large amounts of pannus within the joint spaces, osteoporosis, bone erosions, periosteal new bone formation, heterotopic ossification, and bony ankylosis. Rats treated 28 days with naproxen had significantly milder disease than the vehicle controls. The incidence of severe juxtaarticular bone destruction was 10/10 in the vehicle controls versus 2/10 of the drug-treated group (P less than 0.01). A comparable reduction in cartilage erosion, incidence of pannus, and new bone formation was noted in the drug-treated group. These effects may relate to an inhibition of prostaglandin biosynthesis; prostaglandins have been shown to: 1) stimulate collagenase secretion from macrophages, 2) stimulate bone resorption in vivo and in vitro, and 3) diminish proteoglycan synthesis in cartilage.

Tiopinac displayed marked anti-inflammatory activity when given p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (40 x phenylbutazone), and cotton-pellet-induced granuloma (0.8 x indomethacin). In an 18-day test, tiopinac prevented the development of adjuvant-induced arthritis (10-15 x naproxen) and had similar activity versus pre-induced arthritis. Tiopinac exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. Depending upon the type of analgesic test used, the potency of tiopinac varied. When given p.o. it inhibited phenylquinone-induced writhing in the mouse and rat (respectively 16 and 10 x aspirin). In contrast, tiopinac had approximately 10 times the potency of indomethacin in increasing the pain threshold when yeast-inflamed paws were compressed. The pain threshold of the noninflamed paw was not increased. Tiopinac was highly active versus pain induced by flexing the adjuvant arthritic-inflamed paw (greater than or equal to 1000 x aspirin). It was inactive in the mouse hot-plate test in which opiate-like agents are active. Tiopinac, p.o., lowered yeast-induced pyrexia (130 x aspirin). Tiopinac did not have significant cardiovascular or CNS activity. Whereas the Ed50 versus adjuvant arthritis in rats was 0.1 mg/kg/day p.o., rats tolerated up to 20 mg/kg/day p.o. in the 8-day cotton-pellet test. Lack of anorexia and emesis in dogs with up to 30 mg/kg p.o. and mild oral activity in producing gastric erosion in acute and subacute studies in rats suggests that tiopinac may have relatively little gastrointestinal irritating activity.

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.

The effect of surfactants on percutaneous absorption of naproxen was studied using rat in vivo models. The in vivo normalized relative absorption rates were in good agreement with the in vitro relative flux. An antipyretic model in the rat could not show relatively small increases in percutaneous absorption caused by the surfactants. Based on these results, it is apparent that reliance on the rat, using either in vitro or in vivo models, may lead to erroneous conclusions when considering the effect of surfactants on human percutaneous absorption of drugs such as naproxen.

RS-37619 showed highly potent analgesic activity when given p.o. in tests utilizing underlying inflammation. It inhibited phenylquinone-induced writhing in the mouse and rat (350 and 180 x aspirin respectively) and the pain induced by flexing the adjuvant-inflamed rat paw (approximately 800 x aspirin). The agent increased the pain threshold of compressed yeast-inflamed rat paws (3-10 x naproxen). RS-37619 did not increase the pain threshold of the non-inflamed paw and was inactive in the mouse hot plate test; therefore it is probably not a centrally acting or morphine-like agent. RS-37619 was also highly active p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (36 x phenylbutazone), cotton pellet-induced granuloma (less than or equal to 1 x indomethacin) and in an 18-day test, prevented the development of adjuvant-induced arthritis (approximately 2 x naproxen). RS-37619 exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. When given p.o., RS-37619 lowered yeast-induced pyrexia (20 x aspirin). Gastrointestinal irritation was seen in the rat with doses greater than or equal to 6.4 mg/kg/day p.o. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity.

The syntheses and antiinflammatory assays of some dibenztroponeacetic and -propionic acids and derivatives are described. The most potent compound, d-2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, has a potency of ca, 70 times phenylbutazone in the rat carrageenan paw assay and two to three times indomethacin in long-term animal assays. Some beta-dialkylaminoethyl esters of this compound also show high antiinflammatory activity.

6-Chloro-17 alpha-hydroxypregna-1,4,6-triene-3,20-dione (CHP), a steroid having a progestin-type structure yet not having progestational activity, was found to exhibit moderate anti-inflammatory activity in a number of conventional tests for corticoid potency (e.g., thymolytic, granuloma, carrageenin edema). CHP was essentially equipotent, however, with cortisol in models of inflammation mediated via delayed hypersensitivity such as experimental allergic encephalomyelitis, adjuvant-induced arthritis, mouse skin graft, and mouse skin delayed hypersensitivity. In contrast to cortisol, which inhibits both 19-s and 7-s antibody formation, CHP does not diminish the number of cells producing either antibody.

2-Acetyl-7-oxo-1,2,3,4,4a,4b,5,6,7,9,10,lOa-dodecahydrophenanthrene possessed radioprotective activity when injected subcutaneously (in sesame oil) into 20-day-old male Swiss mice once daily for the 10 days prior to irradiation by cobalt-60 at 30 days of age. Female mice similarly treated were not protected.