Search

Introduction: Until recently, interest in renal function has focused on impairment to limit drug toxicity and increase medication safety. Augmented renal clearance (ARC) has been increasingly studied in multiple patient populations, including oncology, and could lead to decreased drug efficacy from faster elimination resulting in subtherapeutic concentrations. This scoping review sought to summarize ARC literature in cancer and identify areas of research to better inform pharmacy practitioners. Data Sources: Electronic databases were searched for English articles related to augmented/enhanced renal function/clearance following a framework for scoping reviews. Data Synthesis: Fourteen articles were analyzed, divided according to article objective: descriptive studies or ARC's impact on pharmacokinetics/pharmacodynamics. ARC was most defined as creatinine clearance >130 mL/min/1.73 m2, reported in 10%-100% of patients. Febrile neutropenia in adult and pediatric patients, and age <50-65 years, hematologic malignancy, and lower serum creatinine in adult patients were notable risk factors for ARC. The impact of ARC has only been evaluated with antimicrobial agents consistently resulting in lower than anticipated trough levels. Identified gaps include: elucidation of ARC's mechanism and associated biomarkers, an inclusive ARC definition for relative renal enhancement, and study of additional drug classes to ascertain the breadth of ARC impact on drug therapy. Conclusions: ARC is proving to be a frequent phenomenon in patients with cancer which pharmacists could play a vital role. Further research is needed to better understand the impact of ARC in patient care and a potential need to stage ARC based on degree of renal enhancement to establish specific drug dosing recommendations. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase‐3 α/β is involved in dysregulation of neuronal tau protein in Alzheimer's disease (AD). There is an unmet clinical need for a blood‐brain barrier (BBB) permeable positron emission tomography (PET) probe for imaging of GSK‐3α/β in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [18F]F‐CNBI and [18F]F‐CNPIFE, and evaluated their BBB permeability and affinity towards GSK‐3α/β. [19F]F‐CNPIFE showed higher in‐vitro binding towards GSK‐3α/β (IC50=19.4±2.5 nM; n=3, for GSK‐3α, IC50=19.4±3.8 nM; n=3, for GSK‐3β) compared to [19F]F‐CNBI (IC50=107.6±26.0 nM; n=4, for GSK‐3α, IC50=105.3±18.2 nM; n=3, for GSK‐3β). [18F]F‐CNPIFE showed 9.5‐fold higher brain uptake than [18F]F‐CNBI, in normal FVB/NJ mice, which was increased by additional 1.5‐fold on co‐administration of [19F]F‐CNPIFE with respect to [18F]F‐CNBI. Overall, [18F]F‐CNPIFE is a promising PET probe for GSK‐3α/β imaging and warrants further evaluation in an AD mouse model. [ABSTRACT FROM AUTHOR]

Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer's disease (AD) and has drawn considerable attention from the research community to further study its role in AD pathophysiology. Herein, we describe the development of an insulin-based novel positron emission tomography (PET) probe, [ 68 Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [ 68 Ga]Ga-NOTA-insulin showed a significantly higher uptake (0.396 ± 0.055 SUV) in the AD mouse brain compared to the normal (0.140 ± 0.027 SUV) mouse brain at 5 min post injection and also showed a similar trend at 10, 15, and 20 min post injection. In addition, [ 68 Ga]Ga-NOTA-insulin was found to have a differential uptake in various brain regions at 30 min post injection. Among the brain regions, the cortex, thalamus, brain stem, and cerebellum showed a significantly higher standard uptake value (SUV) of [ 68 Ga]Ga-NOTA-insulin in AD mice as compared to normal mice. The inhibition of the insulin receptor (IR) with an insulin receptor antagonist peptide (S961) in normal mice showed a similar brain uptake profile of [ 68 Ga]Ga-NOTA-insulin as it was observed in the AD case, suggesting nonfunctional IR in AD and the presence of an alternative insulin uptake route in the absence of a functional IR. The Gjedde-Patlak graphical analysis was also performed to predict the input rate of [ 68 Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [ 68 Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [ 18 F]AV1451 and [ 11 C]PIB to noninvasively study the role of insulin in AD pathophysiology.