Hemodynamic evaluation of recombinant human tumor necrosis factor (TNF)-alpha, TNF-SAM2 and liposomal TNF-SAM2 in an anesthetized dog model.
We have evaluated the hemodynamic effects of systemically administered recombinant human tumor necrosis factor (TNF)-alpha, TNF-SAM2 and liposome-bound TNF-SAM2 in an anesthetized mongrel dog model. A dose of 10 micrograms TNF protein/kg of each formulation was injected in a peripheral vein and mean systemic arterial pressure (SAP), heart rate (HR) and cardiac output (CO) were measured. TNF-alpha induced a marked drop in SAP in all three dogs (mean decrease = 59.3 +/- 5.2 mm Hg; to 61.5% of baseline; p = 0.008); whereas TNF-SAM2 caused a smaller and transient 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-SAM2, which retains antitumor activity in vivo, a net slight hypertensive phase and sustained elevated CO occurred, followed by a return to an essentially normotensive state (101.0% of baseline SAP). This model demonstrates that the principal acute systemic toxicity of TNF, i.e., hypotension, can be markedly attenuated by liposomal formulation of a second-generation TNF.
Lodato
R F
RF
Department of Internal Medicine, University of Texas Health Science Center, Houston 77030, USA.
Feig
B
B
Akimaru
K
K
Soma
G
G
Klostergaard
J
J
D000818:Animals; D004285:Dogs; D004337:Drug Carriers; D006439:Hemodynamics; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology; D008081:Liposomes / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects
D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha