Development of a High-Fidelity Benchtop Model for Simultaneous Flow, Pressure, and Imaging Assessment of Transarterial Embolization Procedures.

PURPOSE: The development of new endovascular technologies for transarterial embolization has relied on animal studies to validate efficacy before clinical trials are undertaken. Because embolizations in animals and patients are primarily conducted with fluoroscopy alone, local hemodynamic changes are not assessed during testing. However, such hemodynamic metrics could be important indicators of procedure efficacy that could support improved patient outcomes, such as via the determination of procedural endpoints. The purpose of this study is to create a high-fidelity benchtop system for multiparametric (i.e., hemodynamic and imaging) assessment of transarterial embolization procedures. METHODS: The benchtop system consists of a 3D printed, anatomically accurate vascular phantom; a flow loop with a cardiac output simulator; a high-speed video camera; and pressure transducers and flow meters. This system enabled us to vary the heart rate and blood pressure and to simulate clinically relevant hemodynamic states, such as healthy adult, aortic regurgitation, and hypovolemic shock. RESULTS: With our radiation-free angiography-mimetic imaging system, we could simultaneously assess gauge pressure and flow values during transarterial embolization. We demonstrated the feasibility of recapitulating the digital subtraction angiography workflow. Finally, we highlighted the utility of this system by characterizing the relationship between an imaging-based metric of procedural endpoint and intravascular flow. We also characterized hemodynamic changes associated with particle embolization within a branch of the hepatic artery and found them to be within reported patient data. CONCLUSION: Our benchtop vascular system was low-cost and reproduced transarterial embolization-related hemodynamic phenomena with high fidelity. We believe that this novel platform enables the characterization of patient physiology, novel catheterization devices, and techniques.

Rapid Nucleic Acid Reaction Circuits for Point-of-care Diagnosis of Diseases.

An urgent need exists for a rapid, cost-effective, facile, and reliable nucleic acid assay for mass screening to control and prevent the spread of emerging pandemic diseases. This urgent need is not fully met by current diagnostic tools. In this review, we summarize the current state-of-the-art research in novel nucleic acid amplification and detection that could be applied to point-of-care (POC) diagnosis and mass screening of diseases. The critical technological breakthroughs will be discussed for their advantages and disadvantages. Finally, we will discuss the future challenges of developing nucleic acid-based POC diagnosis.

A Citrulline-Based Translational Population System Toxicology Model for Gastrointestinal-Related Adverse Events Associated With Anticancer Treatments.

Gastrointestinal (GI)-related adverse events (AEs) are commonly observed in the clinic during cancer treatments. Citrulline is a potentially translatable biomarker of GI AEs. In this study, irinotecan-induced citrulline changes were studied for a range of doses and schedules in rats. A translational system toxicology model for GI AEs using citrulline was then developed based on new experimental data and parameters from a literature intestinal cell dynamic model. With the addition of feedback-development and tolerance-development mechanisms, the model well captured the plasma citrulline profiles after irinotecan treatment in rats. Subsequently, the model was translated to humans and predicted the observed GI AE dynamics in humans including dose-scheduling effect using the cytotoxic and feedback parameters estimated in rats with slight calibrations. This translational toxicology model could be used for other antineoplastic drugs to simulate various clinical dosing scenarios before human studies and mitigate potential GI AEs.

Comparison of uptake transporter functions in hepatocytes in different species to determine the optimal model for evaluating drug transporter activities in humans.

A thorough understanding of species-dependent differences in hepatic uptake transporters is critical for predicting human pharmacokinetics (PKs) from preclinical data. In this study, the activities of organic anion transporting polypeptide (OATP/Oatp), organic cation transporter 1 (OCT1/Oct1), and sodium-taurocholate cotransporting polypeptide (NTCP/Ntcp) in cultured rat, dog, monkey and human hepatocytes were compared. The activities of hepatic uptake transporters were evaluated with respect to culture duration, substrate and species-dependent differences in hepatocytes. Longer culture duration reduced hepatic uptake transporter activities across species except for Oatp and Ntcp in rats. Comparable apparent Michaelis-Menten constant (Km,app) values in hepatocytes were observed across species for atorvastatin, estradiol-17ß-glucuronide and metformin. The Km,app values for rosuvastatin and taurocholate were significantly different across species. Rat hepatocytes exhibited the highest Oatp percentage of uptake transporter-mediated permeation clearance (PSinf,act) while no difference in %PSinf,act of probe substrates were observed across species. The in vitro hepatocyte inhibition data in rats, monkeys and humans provided reasonable predictions of in vivo drug-drug interaction (DDIs) between atorvastatin/rosuvastatin and rifampin. These findings suggested that using human hepatocytes with a short culture time is the most robust preclinical model for predicting DDIs for compounds exhibiting active hepatic uptake in humans.

Preclinical absorption, distribution, metabolism, excretion and pharmacokinetics of a novel selective inhibitor of breast cancer resistance protein (BCRP).

1. Breast cancer resistance protein (BCRP) plays an important role in drug absorption, distribution and excretion. It is challenging to evaluate BCRP functions in preclinical models because commonly used BCRP inhibitors are nonspecific or unstable in animal plasma. 2. In this work, in vitro absorption, distribution, metabolism and elimination (ADME) assays and pharmacokinetic (PK) experiments in Bcrp knockout (KO) (Abcg2-/-) and wild-type (WT) FVB mice and Wistar rats were conducted to characterize the preclinical properties of a novel selective BCRP inhibitor (ML753286, a Ko143 analog). 3. ML753286 is a potent inhibitor for BCRP, but not for P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP) or major cytochrome P450s (CYPs). It has high permeability, but is not an efflux transporter substrate. ML753286 has low to medium clearance in rodent and human liver S9 fractions, and is stable in plasma cross species. Bcrp inhibition affects oral absorption and clearance of sulfasalazine in rodents. A single dose of ML753286 at 50-300 mg/kg orally, and at 20 mg/kg intravenously or 25 mg/kg orally inhibits Bcrp functions in mice and rats, respectively. 4. These findings confirm that ML753286 is a useful selective inhibitor to evaluate BCRP/Bcrp activity in vitro and in rodent model systems.