This proposal is concerned with the evaluation of the therapeutic effectiveness of fructose-1,6-diphosphate sodium salt (FDP) in septic shock in man. The present working hypothesis is that in any etiological type of shock there is a deficit in endogenous energy production via oxidative metabolic pathway arising either from hypoperfusion or impaired oxygen utilization. Anaerobic glycolysis tends to compensate for the energy deficit arising from failure of the oxidative metabolism by increasing its catabolic relate, but later becomes inhibited by acidosis at the phosphofructokinase step. Hypothetically, administration of FDP should provide the substrate that bypasses the metabolic block. This hypothesis has been tested in (1) acute myocardial ischemia in dogs, (2) normothermic cardiac arrest, (3) hypotensive hemorrhagic shock, (4) normotensive hemorrhagic shock, (5) lethal endotoxin shock, (6) lethal traumatic shock, (7) tourniquet shock, (8) ischemic renal failure, (9) organ preservation, (10) man, and other energy deficient states. In these paired studies, hemodynamic, metabolic and histological findings in the FDP treated animals were significantly improved compared to controls and mortality rates were reduced (p less than 0.001). In normal man and in patients with compromised myocardial function and in shock, FDP had the same effect on the carbohydrate metabolism, hemodynamic parameters and perhaps on survival. Therefore, it is the goal of this proposal to test in a randomized, double blinded, placebo matched fashion whether FDP will be effective in treatment of septic shock in man. As FDP appears to be more effective in different etiological types of shock when used as early as possible, thus, the presumptive diagnosis must be made to institute the FDP therapy. A definitive diagnosis is made retrospectively. Time of presumptive diagnosis to investigational therapy at the time of antibiotic therapy will be stratified in analysis. Patients in definitive septic shock who have been refractive to routinely accepted therapy will also be included in this study. This protocol exercises the hypothesis that FDP aids recovery from septic shock per se. The protocol defines the primary and secondary end points of the study. The data obtained with this agent in animals and man indicate that this intervention could be of clinical importance in the treatment of the shock syndrome.
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| Markov, Angel K; Causey, Alan L; Didlake, Ralph H et al. (2002) Prevention of alpha-naphthylthiourea-induced pulmonary edema with fructose-1,6-diphosphate. Exp Lung Res 28:285-99 |
| Markov, A K; Farias, L A; Bennett, W S et al. (1991) Prevention of galactosamine-induced hepatotoxicity in rats with fructose-1,6-diphosphate. Pharmacology 43:310-7 |
| Sun, J X; Farias, L A; Markov, A K (1990) Fructose 1-6 diphosphate prevents intestinal ischemic reperfusion injury and death in rats. Gastroenterology 98:117-26 |
| Markov, A K (1986) Hemodynamics and metabolic effects of fructose 1-6 diphosphate in ischemia and shock--experimental and clinical observations. Ann Emerg Med 15:1470-7 |
