Clinical experience with platelet-activating factor antagonists. Past, present, and near future.

Abstract

The overall balance of published clinical results following 8 yr of development shows disappointing results in therapeutic areas where the greatest expectations were first hypothesized. However, such a negative statement is largely subsided by the most recent breakthrough in life-saving conditions. It is rather bewildering to note that clinical efficacy was better ascertained in the very areas where pathophysiological rationale was the most hypothetical. Conversely, asthma, which was the indication where PAF antagonists have been largely predicted to be an ideal drug, is now of much less interest. Indications, such as “prevention of acute tubular necrosis following kidney transplant” and “prevention of mortality in gram-negative documented severe sepsis,” could appear far away from each other. However, these indications are consistent with a common hypothesis, which is that PAF acts as an amplifier of the local inflammatory/immune response, although its precise interaction with other mediators (cytokines, integrins, nitric oxide [NO]) and the exact timing of sequences in the various pathological processes remain elucidated. Also, the actual limit of the potential therapeutic interest of PAF antagonists is that clinical manifestations of inflammation will still require a number of years to be elucidated, together with the potential benefit of coadministration with other drugs.