Therapeutic trial of reconstituted human high-density lipoprotein in a canine model of gram-negative septic shock
Quezado, Z.M.; Natanson, C.; Banks, S.M.; Alling, D.W.; Koev, C.A.; Danner, R.L.; Elin, R.J.; Hosseini, J.M.; Parker, T.S.; Levine, D.M.
Journal of Pharmacology and Experimental Therapeutics 272(2): 604-611
1995
ISSN/ISBN: 0022-3565 PMID: 7853173 Document Number: 450347
In a controlled, randomized trial, the authors investigated the effects of reconstituted human high-density lipoprotein (R-HDQ on survival, endotoxemia, cytokine production and pathophysiologic and metabolic events in an animal model of gram-negative septic shock. At 0.5, 8 and 16 hr after implantation of a clot infected with Escherichia coli, canines received intravenous R-HDL (n = 13), control lipid (n = 7) or human serum albumin (HSA, n = 7) divided into three doses (0.3, 0.1 and 0.1 g/kg, respectively) at an hourly rate of 0. 1 g/kg. All animals were treated with antibiotics and fluids. Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor and a smaller decrease in white blood cell counts than did animals treated with lipids and HSA (all P lt .05). The survival times of lipid- and HSA-treated animals were similar (P = .3) and were significantly greater than those of R-HDL-treated animals (P = .02). During the first 6 hr after clot implantation, R-HDL-treated animals had significantly greater abnormalities in liver function test findings compared with lipid- and HSA-treated animals (all P lt .05), For the first 24 hr, R-HDL-treated animals had significant increases in HDL levels; however, there were no significant relationships between these levels and the constituents of HDL (apolipoprotein Al and phosphatidylcholine) or liver function abnormalities and survival times (all r lt .2, P gt .3). In normal animals, administration of R-HDL (in similar doses) caused transient elevation of liver enzymes; in animals given sterile clot i.p., R-HDL caused seizures. Thus, in septic and nonseptic animals, this preparation of R-HDL produced hepatic and neurologic toxicity. However, in septic animals, R-HDL also improved leukopenia and decreased endotoxemia and circulating levels of tumor necrosis factor. If the toxicities associated with R-HDL can be reduced, its antiendotoxin effects should be investigated for their potential benefits in live bacterial infections.