The antiphlogistic, antinociceptive and antipyretic properties of fenclorac

Abstract

Fenclorac (a,m-dichloro-p-cyclohexlphenylacetic acid, diethylammonium salt) is a potent nonsteroidal anti-inflammatory agent with significant analgesic and antipyretic activity. Fenclorac had an ED50 of 7.9 mg/kg in the carrageenan paw edema assay and had a duration of action of 18-22 hours. Comparative tests in the carrageenan paw edema assay in the rat indicated that the potency of fenclorac was 13 times that of aspirin, 3.4 times phenylbutazone, 3 times ibuprofen and 0.3 times indomethacin. Fenclorac was less potent than indomethacin, but more potent than phenylbutazone or aspirin in treatment of developing or established adjuvant arthritis. The anti-inflammatory effectiveness of fenclorac did not depend upon the integrity of the adrenopituitary axis and was not affected by the route of administration or sex of the test animal. Fenclorac was 77 times more potent than aspirin and more than twice as potent as indomethacin in reducing fever in rats rendered hyperthermic with brewer's yeast. Fenclorac did not affect normal body temperatures. Fenclorac did not interfere with cellular immune mechanisms as measured by its lack of effectiveness in experimental allergic encephalomyelitis. Antinociceptive testing indicated that fenclorac had peripheral but not central analgesic activity. Fenclorac had an acute oral LD50 in rats and mice of 285 and 430 mg/kg, respectively. The acute gastric lesion UD50 for fenclorac was 7 mg/kg in the fasted rat. Studies using 51Cr-tagged erythrocytes indicated that fenclorac did not produce significant fecal blood loss in the rat at twice the therapeutic ED50 dose for up to 12 days after dosing. Extensive and prolonged fecal blood loss was observed with a corresponding dose of indomethacin for up to nine days after administration. Comparison of the anti-inflammatory pharmacology, Therapeutic Ratio and the data obtained from the 51Cr-fecal blood loss studies indicated that fenclorac was well tolerated after acute or subacute administration to the rat.

The inhibition of prostaglandin synthetase in vivo by nonsteroidal anti-inflammatory agents

“…Also, in a system in which the dilator response of E prostaglandins are normally more pronounced than the constrictor effects of F prostaglandins, the inhibition of PG synthesis would result in a net pressor effect [19]. Indomethacin was much weaker than fenclorac in the in vitro test for PG synthetase [ 18], but had more activity in paw edema assay [9]; however, both effectively blocked the arachidonate-induced hypotension (Table 1). There is a good parallel relationship between the inhibition of PG synthetases in vitro and their effects on the vasodepressor activity of arachidonate [3].…”

“…Fenclorac (c~-m,dichloro-p-cyclohexylphenylacetic acid, diethylammonium salt), is a new nonsteroidal anti-inflammatory compound [9]. It was superior to phenylbutazone, ibuprofen and aspirin in anti-inflammatory activity in carrageenan paw edema and adjuvant arthritis, and did not cause any significant gastrointestinal blood loss at dose levels 4 times EDso anti-inflammatory dose in the rat [10].…”

GLC Assay of Fenclorac in Human Plasma

“…Fenclorac (~~-a,3-dichloro-4-cyclohexy1phenylacetic acid) is a potent nonsteroidal anti-inflammatory agent with significant analgesic and antipyretic activities (1)(2)(3). In humans and animals, the compound is rapidly absorbed, extensively metabolized, and quantitatively eliminated within 24-48 hr (4,5).…”