Combined Hemoperfusion and Continuous Veno-Venous Hemofiltration for Carbamazepine Intoxication

<b><i>Introduction:</i></b> Carbamazepine (CBZ) is a widely used anticonvulsant with a low molecular weight that allows for extracorporeal removal of free drug by both dialytic and hemoperfusion techniques, particularly in a massive overdose where serum protein binding is saturated. This report presents a case of CBZ intoxication where we were able to compare the mass removal of CBZ using hemoperfusion, with the mass removal of CBZ achieved with continuous renal replacement therapy (CRRT) during combined treatment. <b><i>Methods:</i></b> The Jafron HA230 resin hemoperfusion cartridge was applied in series with the continuous veno-venous hemofiltration (CVVH) circuit. Baseline and ongoing serum drug levels along with further samples from pre- and post-hemoperfusion cartridges and from CVVH effluent were collected. <b><i>Results:</i></b> Combined CVVH and resin hemoperfusion therapy in series was associated with a 50% reduction in the CBZ level from 16 mg/L to 8 mg/L over 3 h, far more rapid than that observed with CVVH alone or in the absence of extracorporeal drug clearance in the preceding hours. The combination therapy removed close to 35 mg/h of CBZ. <b><i>Conclusion:</i></b> The combination of CRRT and hemoperfusion can be easily deployed, appears safe, and is able to combine the CBZ mass removal achieved with each technique, thus to maximize CBZ extraction.

Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging

Contrast-enhanced magnetic resonance imaging is an essential tool for disease diagnosis and management; all marketed clinical magnetic resonance imaging (MRI) contrast agents (CAs) are gadolinium (Gd) chelates and most are extracellular fluid (ECF) agents. After intravenous injection, these agents rapidly distribute to the extracellular space and are also characterized by low serum protein binding and predominant renal clearance. Gd is an abiotic element with no biological recycling processes; low levels of Gd have been detected in the central nervous system and bone long after administration. These observations have prompted interest in the development of new MRI contrast agents based on biotic elements such as iron (Fe); Fe-HBED (HBED = N,N′-bis(2-hydroxyphenyl)ethylenediamine-N,N′-diacetic acid), a coordinatively saturated iron chelate, is an attractive MRI CA platform suitable for modification to adjust relaxivity and biodistribution. Compared to the parent Fe-HBED, the Fe-HBED analogs reported here have lower serum protein binding and higher relaxivity as well as lower relative liver enhancement in mice, comparable to that of a representative gadolinium-based contrast agent (GBCA). Fe-HBED analogs are therefore a promising class of non-Gd ECF MRI CA.

SCIDOT-03. HYPERLOADED POLY(2-OXAZOLINE) MICELLES AS PERSONALIZED DRUG CARRIERS FOR BRAIN TUMORS

Systemic therapies for brain tumors are complicated by dose-limiting extraneural toxicity, serum protein binding and restricted blood-brain barrier (BBB) permeability. For patients with SHH-subgroup medulloblastoma, SHH-pathway inhibition may be more effective and less toxic than current non-targeted therapy. However, vismodegib, which effectively targets SHH-driven basal cell carcinoma, has limited benefit for patients with SHH-driven medulloblastoma. Formulating vismodegib in poly(2-oxazoline) micelles (POx-vismo) improved delivery and efficacy, using medulloblastoma-prone hGFAP-Cre/SmoM2 (G-Smo) mice for a preclinical model. Compared to conventional vismodegib (c-vismo), POx-vismo increased maximum tolerated dose (MTD), tumor:serum ratio and penetration to brain and tumor. Further studies have shown the ability of POx micelles to load CDK4/6 inhibitor. Loading into POx micelles improved MTD and efficacy of palbociclib. Taken together, our results show the potential for poly(2-oxazoline) micelles delivery to make failed brain tumor treatments newly effective. This work was supported by the NCI Alliance for Nanotechnology in Cancer (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence), by NINDS (R01NS088219, R01NS102627) and by the St. Baldrick’s Foundation. References: 1 H. Bader et al. Angew. Macromol. Chem. 1984, 123/124:457; A. Kabanov et al. FEBS Lett. 1989, 258:343; M. Yokoyama et al. Cancer Res. 1990, 50:1693. 2 M. Yokoyama et al. J. Exp. Clin. Med. 2011, 3:8. 3 T. Lorson et al. Biomaterials. 2018, 178:204. 4 R. Luxenhofer et al. Biomaterials 2010, 31:4972; A. Schulz et al. ACS Nano 2014, 8 (3):2686; Z. He et al. Biomaterials 2016, 101:296