biofor-389 and Edema

BF-389, dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-2H-1,2- oxazin-3(4H)-one, is a potent, orally active, antiarthritic and analgesic agent with low ulcerogenic potential. A comparison of the activity profiles of BF-389 and naproxen showed similarities in: (1) suppression of developing and chronic adjuvant arthritis (AA); (2) maximal inhibitory response, as shown by the E(max) values in the developing and established AA models; (3) inhibition of bone degenerative changes associated with chronic adjuvant arthritis; and (4) analgesic activity in the acetic acid and phenylquinone writhing assays. Though BF-389 has been shown to be a potent inhibitor of cyclooxygenase, IC50 = 0.84 +/- 0.25 microM against the production of PGE2 in vitro, there is a great difference from most cyclooxygenase inhibitors; it also inhibits the 5-lipoxygenase enzyme. For BF-389, the IC50 for in vitro LTB4 formation was found to be 3.65 +/- 1.19 microM. The ulcerogenic potential of BF-389 was compared to that of naproxen using a five-day in vivo ulcerogenic rat assay. The UD50 for naproxen was found to be approximately 30 mg/kg/day, p.o. Based upon efficacy in the DEV AA and EST AA models, UD50/ED50 values for naproxen were estimated to be 0.7 and 1.9, respectively. For BF-389 the UD50 was shown to be 520 (389-695) mg/kg/day, p.o., and the corresponding UD50/ED50 values were calculated to be 84 and 28, respectively, thus demonstrating the wide margin of safety between efficacy and ulcerogenicity in rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arthritis, Experimental; Disease Models, Animal; Edema; Female; Male; Mice; Oxazines; Pain Measurement; Peptic Ulcer; Phenols; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley

BF389 (Biofor 389) is a potent anti-inflammatory agent in various animal models including adjuvant and type II collagen arthritis in rats. In vitro assays indicate that this compound is a mixed inhibitor of arachidonic acid metabolism. The compound was evaluated for effects on the acute inflammatory response in the carrageenan paw edema assay in rats using a standard protocol in which the animals were given single or multiple (daily for 5 days) p.o. doses of the compound. Carrageenan was injected into the footpad of each animal 1 hr after dosing and volumes of both hind paws were determined 3 hr later. Basal serum prostaglandin (PG) E2 levels and PGE2 levels in arachidonate-stimulated blood from these same animals also were measured. No anti-inflammatory activity was observed in BF389-treated rats despite the occurrence of profound suppression of basal and stimulated PGE2 production. Animals treated with conventional nonsteroidal anti-inflammatory drugs in this assay had both suppressed PGE2 production and significant anti-inflammatory activity. In another study, groups of rats were given p.o. doses of 1, 10, 100 or 250 mg/kg of BF389 for 5 days in order to determine peak concentrations, T1/2s and total areas under the plasma (tissue) drug concentration curves in plasma and paws. Peak plasma concentrations occurred 2 to 4 hr postdosing and the half-life was 8 to 15 hr over the 1- to 250-mg/kg/day dose range. Peak paw concentrations occurred 6 to 12 hr postdosing and the levels were 9- to 14-fold greater in the paw than in the plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Edema; Half-Life; Male; Oxazines; Phenols; Rats; Rats, Inbred F344; Rats, Inbred Lew