Anti-inflammatory effect of LA 2851 and reference drugs on some models of inflammation. Investigation of the mechanism of action.

LA 2851 (2-4-diamino-7-methyl-pyrazolo (1,5-a) 1,3,5-triazine), a bronchodilator and antiallergic compound, in type I hypersensitivity, has been tested orally for activity against carrageenan oedema and complement dependent, reverse passive Arthus (RPA) and zymosan oedema in rats. Pharmacokinetic determinations were also realized in order to correlate plasma blood levels and pharmacological activity. LA 2851 was found active in the first test but showed a more marked effect in the immunologically mediated RPA reaction and zymosan oedema. Among reference drugs tested, theophylline showed the same pattern in contrast with non-steroidal anti-inflammatory agents. LA 2851 and theophylline, using a superfused lung preparation, were found ineffective on the synthesis of cyclooxygenase products from arachidonic acid. LA 2851 as theophylline inhibited cAMP phosphodiesterase (PDE) but this inhibition does not seem to be involved in their anti-inflammatory activity since papaverine, a potent inhibitor of PDE, was totally inactive. The activity on RPA and zymosan inflammation was achieved at the drug plasma level in the range of those required to relax the trachea. The same antagonism was obtained with the 2 drugs at a lower plasma level with LA 2851 than with theophylline for the same dose administered (25 mg/kg). LA 2851 and theophylline did not inhibit all the components of the inflammatory process since maximum inhibition did not exceed 60% up to 200 mg/kg and 100 mg/kg respectively.