HEMODYNAMIC EVALUATION OF RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR (TNF)-ALPHA, TNF-SAM(2) AND LIPOSOMAL TNF-SAM(2) IN AN ANESTHETIZED DOG-MODEL

We have evaluated the hemodynamic effects of systemically administered recombinant human tumor necrosis factor (TNF)-alpha, TNF-SAM(2) and l iposome-bound TNF-SAM(2) in an anesthetized mongrel dog model. A dose of 10 mu g TNF protein/kg of each formulation was injected in a periph eral vein and mean systemic arterial pressure (SAP), heart rate (KR) a nd cardiac output (GO) were measured. TNF-a induced a marked drop in S AP in all three dogs (mean decrease = 59.3 +/- 5.2 mm Hg; to 61.5% of baseline; p = 0.008); whereas TNF-SAM(2) caused a smaller and transien t drop in SAP in four dogs (mean decrease = 25.5 +/- 10.1 mm Hg; to 81 .2% of baseline; p = 0.086). In three dogs administered liposome-bound TNF-SAM(2), which retains antitumor activity in vivo, a net slight hy pertensive phase and sustained elevated CO occurred, followed by a ret urn to an essentially normotensive state (101.0% of baseline SAP). Thi s model demonstrates that the principal acute systemic toxicity of TNF , i.e., hypotension, can be markedly attenuated by liposomal formulati on of a second-generation TNF.