Table 3.
Summary of published pre-clinical in vivo studies investigating the characteristics (chemical, pharmacokinetic or pharmacodynamic) or the anti-inflammatory effects of eritoran
| Study Author (Date) | Animal Model | Purpose of Study | In vivo Challenge | Dose of Eritoran | Description of Outcome |
|---|---|---|---|---|---|
| Kaneko et al. (1999)63 | Sprague-Dawley rats, Beagles | Develop an assay for plasma eritoran levels to allow evaluation of PK/PD in rat/dog plasma | NA | 0.3mg/kg | Validation of HPLC method for measuring eritoran levels (range 30ng-20mcg/mL) and PK profiles in rat and dog plasma |
| Suganuma et al. (2000)67 | Beagles | Determine the effect (and PK/PD) of eritoran in dogs challenged with lipopolysaccharide (LPS) | LPS, 300ng/kg at 20h and 24h post infusion | 0.03 and 0.1 mg/kg/h x 24h | Presence of drug in plasma (by measured drug levels) does not correlate with drug activity to block LPS induced changes (no PK/PD correlation) |
| Kaneko et al. (2003)32 | Sprague-Dawley rats | Determine PK and disposition of eritoran in rats | NA | 0.1, 0.3, 0.5 or 1mg/kg | Eritoran is mainly taken up by the liver, dephosphorylated and excreted in feces |
| Kaneko et al. (2004)31 | C57/Bl6 female mice, LBP KO mice | Determine whether LPS binding protein (LBP) participates in PK of eritoran | NA | 0.5 mg/kg | LBP binds eritoran similar to LPS, but is not necessary for redistribution or clearance of drug from plasma |
| Savov et al. (2005)17 | C3HeB/FeJ mice | Test efficacy of intratracheal eritoran pretreatment in preventing chronic LPS induced airway disease | LPS 4.7mcg/m2 aerosol | 10, 100mcg; 50mcg tiw for 5 wks | Eritoran attenuated physiologic and biologic effects of acute and chronic LPS |
| Zhou et al. (2005)64 | C57/Bl6 mice | Determine the effects of eritoran in LPS and oleic acid (OA) mediated acute lung injury (ALI) | 20mcg/g | 4mcg/g | Pre-treatment with eritoran attenuated synergistic injurious effects of LPS and OA on the lungs |
| Shimamoto et al. (2006)21 | C57/Bl6 mice | Determine effect of eritoran on myocardial infarction (MI) and reperfusion injury after LAD occlusion | Left anterior descending artery (LAD) occlusion | 5mg/kg | Eritoran attenuated infarct size, JNK phosphorylation, NF-κB activation and myocardial inflammatory gene expression |
| Wasan et al. (2008)33 | Female rabbits | Determine influence of plasma lipids and eritoran micelle size on PK and ex vivo activity | NA | 0.5mg/kg | Small micelles cleared slower and had more PD activity than large ones; diet or lipid levels did not affect eritoran PK/PD |
| Sun et al. (2009)20 | C57/Bl6 mice | Determine effect of eritoran in contact lens associated corneal infiltrates | 40 mcg LPS or killed P. aeruginosa suspended in 0.3% tobramycin in PBS | 1–2 mcL of a 1.1mg/mL solution | Eritoran pre- and post-treatment attenuated corneal inflammation induced by LPS or killed bacteria. |
| Kitazawa et al. (2009)19 | Wistar rats | Determine the effect of eritoran on D-galactosamine (GalN) induced acute liver failure in rats | GalN, 1g/kg intraperitoneal | 3mg/kg Eritoran iv | Eritoran reduced liver injury secondary to GalN |
| Ma et al. (2009)65 | Sprague-Dawley rats | Determine if the pathogenesis of subarchnoid hemorrhage (SAH) is TLR4 mediated | Surgically induced SAH | 20mcg in 20mcL | Eritoran decreased NF-κB activity, inflammatory cytokine levels and neurological dysfunction secondary to experimental SAH |
| Liu et al. (2010) 22 | Fisher rats | Determine if eritoran inhibits inflammatory effects of ischemia-reperfusion in kidneys | Surgical clamping of renal artery and vein | 5mg/kg iv | Eritoran decreased mortality, renal function decline, renal tubular injury and inflammatory gene expression secondary to ischemia-reperfusion |
PK, pharmacokinetics; PD, pharmacodynamics; NA, not applicable; HPLC, high performance liquid chromatography; JNK, c-Jun NH2-terminal kinase; NF-κB, nuclear factor kappa B.