Abstract |
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)
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Authors | A M Bendele, D N Benslay, J T Hom, S M Spaethe, K J Ruterbories, T D Lindstrom, S J Lee, R W Naismith |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 260
Issue 1
Pg. 300-5
(Jan 1992)
ISSN: 0022-3565 [Print] United States |
PMID | 1309875
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Diamines
- Interleukin-1
- Oxazines
- Phenols
- Biofor 389
- Piroxicam
- Diclofenac
- Leukotriene B4
- Arachidonic Acid
- Thromboxane B2
- Naproxen
- Collagen
- Dinoprostone
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Topics |
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(adverse effects, blood, pharmacology)
- Arachidonic Acid
(metabolism)
- Arthritis, Experimental
(drug therapy, metabolism)
- Collagen
- Diamines
- Diclofenac
(pharmacology)
- Dinoprostone
(biosynthesis)
- Disease Models, Animal
- Female
- Interleukin-1
- Leukotriene B4
(biosynthesis)
- Male
- Naproxen
(pharmacology)
- Oxazines
(adverse effects, blood, pharmacology)
- Phenols
(adverse effects, blood, pharmacology)
- Piroxicam
(pharmacology)
- Rats
- Rats, Inbred Lew
- Thromboxane B2
(biosynthesis)
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