Pharmacodynamic evaluation of the neutralization of endotoxin by PMX622 in mice.

Polymyxin B (PMB) binds to and neutralizes endotoxin, but its systemic clinical utility is limited by neuro- and nephrotoxicity. PMX622 is a covalent conjugate of PMB and Dextran-70 designed to retain the ability of PMB to neutralize endotoxin and to retain the favorable colloidal, pharmacokinetic, and metabolic properties of Dextran-70. PMX622 has demonstrated efficacy in a number of animal models and effectively neutralized endotoxin in phase I clinical trials. Here, we systematically evaluated the pharmacodynamic properties of PMX622 in a murine model of endotoxin-induced lethality in galactosamine-sensitized mice. PMX622 completely and dose dependently inhibited lethality in this model. A stoichiometric relationship was found between the endotoxin challenge dose and the dose of PMX622 needed for protection. PMX622 neutralized endotoxin from four different genera of gram-negative bacteria but not Neisseria meningitidis. PMX622 was significantly less toxic than PMB in the mouse, suggesting that PMX622 has a better margin of safety than PMB. The timing of PMX622 administration relative to endotoxin was crucial. PMX622 was active for several hours prior to the endotoxin challenge; however, PMX622 did not protect mice if administered >/=15 min after endotoxin challenge. This suggests that PMX622 would best be clinically used prophylactically rather than therapeutically. These studies will be crucial in designing and interpreting human clinical trials assessing PMX622 efficacy.

Long-term islet graft survival in streptozotocin- and autoimmune-induced diabetes models by immunosuppressive and potential insulinotropic agent FTY720.

BACKGROUND: Toxicity of current immunosuppressive agents to islet grafts is one of the major obstacles to clinical islet transplantation (Tx). This study was designed to assess the efficacy of FTY720, a novel immunomodulator with a unique mechanism of action, on islet graft survival and function in streptozotocin (STZ)- and autoimmune-induced diabetic recipients. METHODS: Islet allograft from BALB/C mice or islet isografts were transplanted into STZ-induced diabetic CBA mice and autoimmune nonobese diabetic (NOD) mice. FTY720 was administered orally at 0.5 mg/kg per day in STZ diabetic recipients or 3 mg/kg per day in NOD recipients after Tx. Functional status of the islet graft was monitored by measuring blood glucose daily. Insulin secretion from mouse islets was measured with an insulin scintillation proximity assay. RESULTS: Under the treatment of FTY720, long-term normoglycemia (>100 days) was achieved in 100% of STZ diabetic recipients and 50% of diabetic NOD recipients compared with a respective 11 and 7 days in untreated animals after allogeneic islet Tx. Normoglycemia persisted only temporarily (<4 weeks) in untreated NOD recipients of NOD islets, but was maintained for >100days with FTY720 treatment. Histologically, leukocyte infiltration observed in untreated animals was largely inhibited in FTY720-treated ones. Additionally, FTY720 stimulated insulin secretion from isolated islets by approximately twofold under both normoglycemic and hyperglycemic conditions. CONCLUSIONS: FTY720 is highly effective in protecting allo- and autoimmune response-mediated islet graft destruction without direct toxicity to the islets. The effect is likely attributable to its action in preventing effector lymphocyte infiltration into the grafted tissue.