Anti-inflammatory activity of BF389, a Di-T-butylphenol, in animal models of arthritis.
Biofor 389 (BF389), dihydro-4-[[3,5-bis(1,1-dimethyl)-4-hydroxyphenyl] methylene]-2-methyl-2H-1,2-oxazin-3(4H)-one, was tested for anti-inflammatory activity in various animal models of arthritis. Initial evaluation in the lipoidalamine (LA) arthritis model in rats (5-day dosing protocol) resulted in an oral ED50 of 4.9 mg/kg for inhibition of paw swelling. No effects on splenomegaly were observed, suggesting that the compound was efficacious as a result of anti-inflammatory rather than immunomodulatory effects. BF389 was efficacious in interleukin 1 (IL-1)-enhanced type II collagen arthritis in rats (oral ED50 less than 1.0 mg/kg) as assessed by paw volume measurement and histologic evaluation of joints. Mice with IL-1-enhanced type II collagen arthritis given 30 mg/kg of BF 389 had significantly lower histological scores for joint damage than did untreated controls. Normal rats given single oral doses of BF389 had significant suppression of arachidonate-stimulated whole blood prostaglandin E2 and thromboxane B2 production 2 hr postdosing (ED50 = 0.1 mg/kg). Leukotriene B4 production in these animals was not decreased. After it became apparent that the compound was a potent inhibitor of prostaglandin production in vivo, a study was done to compare the efficacy and toxicity of BF389 with several currently marketed nonsteroidal anti-inflammatory drugs, piroxicam, naproxen and diclofenac. Lipoidalamine-injected rats were given daily oral doses of BF389 or the comparators for 21 days. Quantitation of effects on arthritis on day 21 resulted in ED50 values of 0.9 mg/kg (BF389), 3.9 mg/kg (naproxen), 4.9 mg/kg (diclofenac) and 0.6 mg/kg (piroxicam).(ABSTRACT TRUNCATED AT 250 WORDS)
Bendele
A M
AM
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana.
Benslay
D N
DN
Hom
J T
JT
Spaethe
S M
SM
Ruterbories
K J
KJ
Lindstrom
T D
TD
Lee
S J
SJ
Naismith
R W
RW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003094:Collagen; D003959:Diamines; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D007375:Interleukin-1; D007975:Leukotriene B4 / Q000096:biosynthesis; D008297:Male; D009288:Naproxen / Q000494:pharmacology; D010078:Oxazines / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D010636:Phenols / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D010894:Piroxicam / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013929:Thromboxane B2 / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003959:Diamines; D007375:Interleukin-1; D010078:Oxazines; D010636:Phenols; C072260:Biofor 389; D010894:Piroxicam; D004008:Diclofenac; D007975:Leukotriene B4; D016718:Arachidonic Acid; D013929:Thromboxane B2; D009288:Naproxen; D003094:Collagen; D015232:Dinoprostone