Figure 8 presents results for urinary β-N-acetylglucosaminidase, and Fig. 9 presents results for retinol binding protein levels. Collectively, these results and those from testing urinary albumin, urinary IgE CUDC-907 mw excretion, and urine osmolarity (data not shown) did not reveal any dose-related patterns or other changes suggestive of renal dysfunction across the range of P188-P doses that were studied. Fig. 8 Urinary β-N-acetylglucosaminidase (NAG) levels in selleckchem patients treated with purified poloxamer 188 (P188-P). Each
bar represents the mean ± standard deviation for measurements conducted in the indicated group Fig. 9 Retinol binding protein levels in patients treated with purified poloxamer 188 (P188-P). Each bar represents the mean ± standard deviation for measurements conducted in the indicated group 4 Discussion We have prepared and studied a more homogeneous form of P188 by removing certain LMW substances found in commercially available, excipient-grade P188 and comparing the purified form (P188-P) see more with the unpurified material (P188-NF). Since elevated creatinine was the dose-limiting
toxicity identified in prior clinical trials of P188-NF, we compared the two materials using 5/6 nephrectomized rats, where 5/6 of kidney function is ablated and the residual kidney is highly sensitive to the effects of potential renal toxicants [32–34]. 4.1 Renal Changes Following Exposure to P188 are Consistent with Osmotic Nephrosis Histologic evaluation of stained kidney sections from nephrectomized rats infused with P188-P or P188-NF show hydropic swelling and vacuolization within the epithelial cells of the nephron’s PCTs. The effect is dose dependent, with vacuolization restricted to the PCT. The presence of PAS-positive droplets inside the cytoplasmic vacuoles demonstrated that the vacuoles contained reabsorbed protein. However, even at the highest dose click here that was studied (1,000 mg/kg/h), there was no histopathologic evidence of tubule necrosis. Electron microscopy confirmed that the brush
border was anatomically intact and that the mitochondria appeared normal, showing no transition forms, amplitude swelling, or formation of matrical granules. Vacuolation of the renal tubule epithelium, like that induced by P188, has been observed in Sprague–Dawley rats during toxicologic evaluation of polyethylene glycol (PEG)-linked proteins. Rather severe lesions were present when lower molecular weight PEG-linked proteins were tested, while minimal, if any, were seen with PEG-linked proteins >70 kD, suggesting that protein with attached PEG was reabsorbed by the proximal tubules. The observed vacuolation that accompanied the response was thought to result from fluid distension within lysosomes due to the hygroscopic nature of PEG .