salicylates and fendosal

Plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator in plasma, is a well established risk factor in thrombotic diseases. Reduction of active PAI-1 levels may lead to a decreased tendency of thrombosis. Compounds that can suppress pharmacologically active PAI-1 levels are therefore considered as putative drugs. In the present study, we describe the PAI-1 neutralizing properties and mechanism of a newly selected compound (i.e. fendosal, HP129) in comparison to four previously reported compounds (i. e. AR-H029953XX, XR1853, XR5118 and the peptide TVASS) using different assays. The inhibitory effect of these compounds on active PAl-1 was analyzed by a plasmin-coupled chromogenic assay (Coaset t-PA), direct chromogenic assays (t-PA, u-PA) and quantification of complex formation by ELISA, SDS-PAGE and surface plasmon resonance. Comparative evaluation of the obtained IC50 values reveals large differences [i.e. IC50 of 15 microM (HP129) vs. >1000 microM (XR5118) determined at 37 degrees C using SDS-PAGE] between the compounds studied. Importantly, the relative potency of the various compounds is also dependent on the method used (10 to 170-fold differences in IC50 values). Characterization of the PAI-1 forms (i.e. active, non-reactive and substrate) generated upon inactivation reveals that the newly described compound HP129 induces a unique pathway (i.e. active to non-reactive conversion via a substrate-behaving intermediate) of inactivation compared to the other compounds. Taken together, these data strongly suggest that the various compounds act through different mechanisms. In addition, the results stress the necessity for a careful selection of the method used for the evaluation of PAI-1 inhibitors, preferably requiring a panel of screening methods.

Topics: Anticoagulants; Chlorphenamidine; Chromogenic Compounds; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Humans; Inhibitory Concentration 50; Nitro Compounds; Piperazines; Plasminogen Activator Inhibitor 1; Salicylates; Serine Proteinase Inhibitors; Surface Plasmon Resonance

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Indoles; Salicylates

Fendosal (HP 129) is one of a series of potent non-steroidal anti-inflammatory agents. Fendosal was compared with aspirin in several anti-inflammatory and analgesic bioassay procedures. Results indicate that fendosal has an anti-inflammatory activity 1.4 times greater than does aspirin in carrageenan-induced rat paw edema. Fendosal is 6.9 to 9.5 times more active than aspirin in the prophylactic and therapeutic adjuvant-induced polyarthritis models of chronic inflammation. The analgesic activity of fendosal is considered to be superior to that of aspirin, with the advantage of a prolonged duration of action. The gastric-irritating properties of fendosal are very low in comparison with those of aspirin. Fendosal has a much wider separation of effective and gastric-irritating doses than does aspirin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Edema; Female; Granuloma; Hydroxybenzoates; Indoles; Rats; Salicylates