Within 20 min after intraperitoneal injection of Salmonella enteritidis endotoxin in rats, blood platelet-activating factor (PAF) increased from 4.3 +/- 1.3 to 13.7 +/- 2.0 ng/ml (P less than 0.01) and lung PAF from 32.3 +/- 4.9 to 312.3 +/- 19.6 ng (P less than 0.01), but not lung lavage PAF. We tested the effect of PAF receptor antagonists, CV 3988 and SRI 63-441, on endotoxin-induced hemodynamic changes and lung vascular injury. Pretreatment with CV 3988 attenuated systemic hypotension, preserved hypoxic pulmonary vasoconstriction, and prolonged survival of awake catheter-implanted endotoxin-treated (20 mg/kg) rats. Pretreatment with SRI 63-441 prevented the depressed hypoxic pulmonary vasoconstriction after low dose (2 mg/kg) endotoxin. Both CV 3988 and SRI 63-441 blocked the increased extravascular accumulation of 125I-albumin and water in perfused lungs isolated from endotoxin-treated rats. We conclude that PAF is produced in the lung during endotoxemia and may be an important mediator of the systemic and pulmonary hemodynamic changes as well as the acute lung vascular injury after endotoxemia.

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Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats.

Chemical and biochemical aspects of platelet activating factor: a novel class of acetylated ether-linked choline-phospholipids.

CV-3988 - A specific antagonist of platelet activating factor (PAF)

Effect of a ginkgolide mixture (bn 52063) in antagonising skin and platelet responses to platelet activating factor in man

Miltefosine (hexadecylphosphocholine, Impavidotrade mark), a novel antiprotozoal drug used for the treatment of visceral and cutaneous leishmaniasis, was identified and evaluated independently in the early 1980s as a potential anticancer drug in Germany and as an antileishmanial drug in the UK. Although miltefosine is not the most active compound of its class against Leishmania parasites in vitro, the early demonstration of activity after oral administration in experimental models of visceral leishmaniasis helped to bring this compound to the attention of WHO TDR for further development in a unique collaboration model with the pharmaceutical industry (Zentaris GmbH). Miltefosine is active against most Leishmania species, including those that cause cutaneous disease.

Miltefosine — discovery of the antileishmanial activity of phospholipid derivatives

New total synthesis and high resolution 1H NMR spectrum of platelet-activating factor, its enantiomer and racemic mixtures.

Summary. The 1-O-alkyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine (PAF-acether) aggregates rabbit platelets and desensitizes them to a second challenge with the same agonist but not to arachidonic acid. The desensitizing activities of 14 analogues of PAF-acether were explored with particular attention to the dose-response dependency of the desensitization process. PAF-acether was 500-fold more active than its 1-O-acyl analogues. The 2-lyso PAF-acether was inactive and the PAF-acether enantiomer 2000 times less effective than the natural isomer, thus confirming the importance of the presence and steric position of the 2-acetate group. The desensitizing activities of the 2-propionyl and the 2-butyryl analogues were close to that of PAF-acether. Substituting an ether to an ester bond at the 2-position indicated that the number of carbon of the 2-substituant seems more determinant than the nature of the linkage for the desensitizing process. Indeed, the 2-ethoxy and the 2-methoxy analogues were 87 and 5000 times less active than PAF-acether respectively. The presence of methyl groups on the nitrogen base is also critical to desensitize platelets. The desensitizing potency of the tested phospholipids was always identical to their aggregating efficiency. It is suggested that these compounds activate cells through a common mechanism.

Effect of structural analogues of PAF‐acether on platelet desensitization

Effects of PAF-acether and structural analogues on platelet activation and bronchoconstriction in guinea-pigs

The presently described pathways for the total synthesis of PAF-acether are long and difficult. Modifications of the original methods are presently described, which simplify the process and improve their yield.

Additional techniques for the total synthesis of PAF-acether

Effect of PAF-acether antagonists, RP 48740 and BN 52021, on platelet activation and bronchoconstruction induced by PAF-acether and structural analogues in guinea-pig

Marie-Claude Borrel

Papers

New total synthesis and high resolution 1H NMR spectrum of platelet-activating factor, its enantiomer and racemic mixtures.

Effect of structural analogues of PAF‐acether on platelet desensitization

Effects of PAF-acether and structural analogues on platelet activation and bronchoconstriction in guinea-pigs

Additional techniques for the total synthesis of PAF-acether

Effect of PAF-acether antagonists, RP 48740 and BN 52021, on platelet activation and bronchoconstruction induced by PAF-acether and structural analogues in guinea-pig