This proposal is concerned with the evaluation of the therapeutic effectiveness of Fructose-1,6-diphosphate Sodium Salt (FDP) in patients with Adult Respiratory Distress Syndrome (ARDS). Pertinent clinical and experimental information concerning the possible involvement of polymorphonuclear leukocytes in the development of acute lung injury characterized by permeability edema, suggests that be selectivity modifying the neutrophils activity in patients with or at risk for ARDS development, a rational therapeutic intervention is feasible. The present hypothesis for the pathogenesis of ARDS is that aggregated neutrophils injure endothelial cells by the generation of toxic oxygen radicals. Scavengers such as superoxide dismutase (SOD), and dimethyl sulfoxide, as well as catalase, provide partial protection in experimentally induced non-cardiogenic pulmonary edema. We have made some basic observations in experimental models and critically ill ARDS patients, and the results suggest a relationship between the pathophysiology of ARDS and the protective effect of FDP. The proposed mechanism by which FDP prevents or attenuates formation of non-cardiogenic edema is that this agent inhibits completely the """"""""respiratory burst"""""""" in stimulated neutrophils. The term """"""""respiratory burst"""""""" refers to an increase in glucose oxidation via the hexosemonophosphate shunt with generation of free radicals O2,.OH, or H2O2. FDP completely abolishes the respiratory burst of stimulated human or animal neutrophils by direct inhibition of 6-phosphogluconate dehydrogenase. This hypothesis is supported by the following experimental and clinical observations: (1) In treating patients in shock with FDP, in those who had concomitant ARDS we noted significant hemodynamic, radiographic and pulmonary function improvement, and perhaps survival. (2) In dogs injected with yield-naphthylthiourea, FDP treatment prevented elevation of pulmonary pressure and resistance, as well as edema formation. (3) The """"""""respiratory burst"""""""" by human or dog neutrophils stimulated with latex particles or PMA or bacteria is inhibited by addition of FDP. (4) Similarly, FDP inhibits the reduction of Cyt-C by superoxides O2,.OH to the same degree as SOD. It is not clear whether one or all of these properties of FDP will affect the outcome of ARDS. Consequently, this double-binded placebo controlled study is designed to assess whether FDP will reduce the mortality in this high-risk population. Mindful of the frequency, morbidity, lethality and the absence of specific therapy for ARDS, conducting of proposed studies seems appropriate.
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