The Effect Of CI-1004 And Its Mechanism

CI-1004 (darbufelone), 4-thiazolidinone, 5-[[3,5-bis (1,1- di - methylethyl)- 4-hydroxyphenylJ-methyIeneJ-2-imino-, (z)-, methanesulfonate (1:1) salt, is a potent cyclooxygenase and 5-lipoxyenase inhibitor of arachidonic acid metabolism, with good gastric tolerance and relatively low toxicity. Multiple kinds of animal models were used to evaluate its anti-inflammatory, analgesic, immunologic effects and toxicity.In acute inflammatory models, 50, 25, 12.5 mg/kg CI showed potent inhibitory effects (p<0.01) on xylene-induced mice pinnea edema and vascular permeability increase caused by acetic acid (i.p.). Moreover, CI (40, 16, 6.4 mg/kg), administered orally, demonstrated inhibitory effect on carrageenin-induced hind paw edema and pleurisy associated with decreased exudation, leukocyte accumulation and protein levels. In addition, although CI could not affect the rat granuloma induced by cotton-pellet and secondary effect of adjuvant arthritis, it could significantly attenuate the primary effect of adjuvant arthritis.At the same time, CI also possessed potent analgesic effect. CI showed more effective antinociception in the acetic acid induced writhing test in mice than that of Indomethacin, and EDso were 2.63, 4.86 mg/kg, respectively. The early-phasebehaviours in mice were not different from those in vehicle control mice in the formalin test. In the late phase, the amount of the time spent in licking the injected paw was significantly reduced. Again, CI could also prolong the elapsed time of mice on hot-plate hyperalgesia assay.Furthermore, CI could interfere the modulation of immunologic response. It decreased the carbon clearance rate of charcoal particles, promoted the production of the hemolysin immunized with SRBC and suppressed the delayed type hypersensitiviry reaction.Most of all, although LDso of CI was 3236.7 mg/kg in female mice, it had not any lethal effect at dose of 10 g/kg in male mice; in acute ulcergenesis experiment, CI showed more potent inhibitory effect than that of Indo with UD50 24.26, 0.4139 mg/kg, respectively; CI also didn't possess delayed healing effect on ulcer which were typical of selective COX-2 inhibitors.In conclusion, CI executed its anti-inflammatory, analgesic effect by mechanism of inhibition the production or release of several kinds of inflammatory cytokines and partly by activated the hypothalamus-pituitary-adrenal system. CI represents a new class of anti-inflammatory drugs which may exhibit less gastrointestinal toxicity and may be efficacious in inflammatory disease states where excessive PG and LT production has been implicated and may offer a significant alternative to nonsteroidal and corticosteroidal anti-inflammatory therapy.