SUMMARYWe have studied the participation of platelet-activating factor (PAF) in antigen-induced arthritis in rabbits, as well as the possible co-operation between PAF and tumour necrosis factor (TNF) in their ability to induce joint inflammation when injected into the knees of healthy rabbits. The administration of two structurally different PAF receptor antagonists, BN52021 and Alprazolam, from 4 h before the intra-articular injection of ovalbumin in preimmunized rabbits, induced an important reduction in the synovial fluid volume, in the amount of cells infiltrating the articular cavity and the synovial membrane, as well as in the prostaglandin E2 (PGE2) concentration. Furthermore, proteoglycans of the articular cartilage, which were found diminished in animals with non-treated arthritis, were well preserved in rabbits treated with PAF antagonists. All the synovial fluids from joints with arthritis had detectable amounts of PAF. The injection of either TNFor PAF into the joints of normal rabbits induced a mild inflammation. When TNF was administered 1 h before PAF, a synergistic response was noted in the synovial fluid volume, in the accumulation of leucocytes, and in the amount of PGE2. The administration of BN50726, a hetrazepine with a potent PAF-receptor antagonist effect, induced a diminution in those parameters. Our results suggest that PAF may be an early and important mediator of joint damage, and that TNF can amplify the inflammatory response induced by PAF. PAF receptor antagonists could play some role in the treatment of inflammatory joint diseases.

01 Apr 1995·Thrombosis ResearchQ3 · MEDICINE

Mechanisms of the platelet aggregation induced by activated neutrophils and inhibitory effect of specific PAF receptor antagonists

Q3 · MEDICINE

Article

Author: Gérard Potron ; Emmanuelle Petitfrère ; Philippe Nguyên

The supernatant of polymorphonuclear neutrophils after their activation by opsonized zymosan induces the aggregation of washed platelets in human. It potentiates platelet aggregation induced by agonists in platelet rich plasma as well as in whole blood. This activation involves the phosphoinositide metabolism. Specific PAF receptor antagonists gingkolides (BN 50726, BN 52021, BN 54068, BN 54062, BN 50730, BN 50749, BN 50744) and benzodiazepine Web2086 antagonize this neutrophil-induced platelet aggregation. BN 50,730, BN 50,749 and Web 2086 can fully inhibit this aggregation at the final concentration of 10(-6) M. Preincubation of platelets with synthetic PAF also inhibits this activation through a desensitization of the receptor. These data suggest the major involvement in our model of PAF acether in the platelet-neutrophil interactions.

01 May 1994·Journal of lipid mediators and cell signalling

Protection against cyclosporin-induced nephrotoxicity: 1. Effect of a PAF antagonist, BN50726.

Article

Author: Dutertre-Catella, H ; Claude, J R ; Braquet, P ; Warnet, J M ; Martin, C ; Massicot, F

The clinical usefulness of cyclosporin A (CsA) in organ transplantation is limited by its intrinsic nephrotoxicity, the mechanisms of which have not yet been completely elucidated. Various processes could be responsible for the CsA-induced nephrotoxicity including an interaction with glutathione metabolism, a lipoperoxidative process, or an interaction with platelet-activating factor (PAF). Therefore, the aim of this study was to assess the potential role of PAF in CsA-induced nephrotoxicity using a new PAF antagonist, BN50726. CsA alone provoked a significant increase in serum urea, urinary gamma-glutamyl transferase activity and oxidized glutathione level of kidney cortex in the rat. In contrast, when rats were treated with CsA plus BN50726, urinary gamma-glutamyltransferase activity was similar to that of controls and oxidized glutathione was significantly lower than that measured in rats treated with CsA alone. However, serum urea remained increased as it was in the CsA group. Our results suggest that BN50726 is able to prevent the damage of renal membranes probably by an antiperoxidative activity. These data indicate the potential therapeutic capacity of a PAF antagonist, BN50726, in reducing CsA nephrotoxicity and suggest interactions between PAF and CsA in the mechanism of renal injury.

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Indication	Highest Phase	Country/Location	Organization	Date
Arrhythmias, Cardiac	NDA/BLA	-	Ipsen SA	-
Stroke	Phase 1	FR	Institut Henri Beaufour	01 Jan 1991
Brain Ischemia	Phase 1	-	Ipsen SA	-
Myocardial Ischemia	Phase 1	-	Ipsen SA	-

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