07 ± 0.2 1.59 ± 0.7 +0.52 ± 0.5  500 1.23 ± 0.3 1.85 ± 0.6 +0.62 ± 0.5  1,000 1.07 ± 0.3 2.48 ± 0.6* +1.41 ± 0.6** P188-P        250 1.5 ± 0.5 2.15 ± 0.5 +0.65 ± 0.7  500 0.93 ± 0.2 1.5 ± 0.2 +0.57 ± 0.3  1,000 0.87 ± 0.3 1.73 ± 0.7* +0.86 ± 0.7** * p = 0.0005, ** p = 0.005 for the comparison between P188-NF

and P188-P Table 2 shows creatinine clearance values following treatment with either P188-P or P188-NF. Creatinine clearance was higher in animals treated with P188-P at doses of 250 and 500 mg/kg/h than in animals treated with P188-NF at similar doses. At 1,000 mg/kg/h, creatinine clearance was high in both groups, with no difference between treatments. Table 2 Serum creatinine clearance in remnant-kidney

animals treated with excipient-grade poloxamer 188 (P188-NF) AZD6738 cell line MCC950 in vivo or purified poloxamer 188 (P188-P) Treatment and dose (mg/kg/h) Creatinine clearance at end of infusion (µl/min/100 g; mean ± standard deviation) P188-NF    250 63 ± 40  500 86 ± 113  1,000 246 ± 141 P188-P    250 168 ± 116  500 164 ± 116  1,000 225 ± 217 Survival following supra-pharmacologic dosing (1,000 mg/kg/h) was higher at both 24 and 48 h post-infusion in animals treated with P188-P than in those treated with P188-NF (Fig. 4). Survival at 24 h was 92 % (23/25) in animals treated with P188-P, compared with 64 % (16/25) in animals treated with P188-NF (p = 0.04). Survival at 48 h was 70 % (21/30) and 50 % (15/30) for P188-P and P188-NF, respectively (p = 0.3). Administration of equivalent amounts of the LMW substances isolated during the supercritical fluid extraction procedure resulted in markedly reduced survival at 24 h (less than 10 %; data not shown). Doses less than 1,000 mg/kg/h had negligible effects

on survival: only one of six rats died after infusion with 500 mg/kg/h, and there was Tyrosine-protein kinase BLK 100 % survival in the 250 mg/kg/h group. Fig. 4 Survival following supra-pharmacologic dosing of excipient-grade poloxamer 188 (P188-NF) and purified poloxamer 188 (P188-P) in www.selleckchem.com/products/MLN-2238.html remnant-kidney animals (n = 25 animals/group in each 24-h group; n = 30 animals/group in each 48-h group). Survival (%) = (number of animals alive at indicated time point/number of animals at t = 0)*100 The reversibility of the renal effects of P188-P and P188-NF was also studied at 24, 48, 96, and 144 h post-infusion following a dose of 1,000 mg/kg/h for 6 h. At 24 h, widespread vacuolization of PCT was observed with both P188-P and P188-NF, with no major differences in the degree of vacuolization between the two compounds. However, by 48 h, widespread vacuolization was still present with P188-NF, while much less vacuolization was observed in animals infused with P188-P. At 96 h, minimal vacuolization was observed with P188-P, while slightly fewer but larger vacuoles were present in the P188-NF–treated animals.