In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial ß-glucuronidase targeting compound Inh 1.

In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterial ß-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species.The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively.The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation, deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat.Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mL were measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.

The in vitro metabolism and in vivo pharmacokinetics of the bacterial ß-glucuronidase inhibitor UNC10201652.

In vitro incubation of the bacterial ß-glucuronidase inhibitor UNC10201652 (4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine) with mouse, rat, and human liver microsomes and hepatocytes generated metabolites at multiple sites via deethylations, oxidations and glucuronidation.Two UNC10201652 metabolites were detected in human, and four in mouse and rat liver microsomal incubations. Intrinsic clearances of UNC10201652 in human, mouse, and rat liver microsomes were 48.1, 115, and 194 µL/min/mg respectively.Intrinsic clearances for human, mouse, and rat hepatocytes were 20.9, 116, and 140 µL/min/106 cells respectively and 24 metabolites were characterised: 9 for human and 11 for both rodent species.Plasma clearance was 324.8 mL/min/kg with an elimination half-life of 0.66 h following IV administration of UNC10201652 to Swiss Albino mice (3 mg/kg). Pre-treatment with 1-aminobenzotriazole (ABT) decreased clearance to 127.43 mL/min/kg, increasing the t1/2 to 3.66 h.Comparison of profiles after oral administration of UNC10201652 to control and pre-treated mice demonstrated a large increase in Cmax (from 15.2 ng/mL to 184.0 ng/mL), a delay in Tmax from 0.25 to 1 h and increased AUC from 20.1 to 253 h ng/ml. ABT pre-treatment increased oral bioavailability from 15% to >100% suggesting that CYP450's contributed significantly to UNC10201652 clearance in mice.

Deep Few-view High-resolution Photon-counting Extremity CT at Halved Dose for a Clinical Trial.

The latest X-ray photon-counting computed tomography (PCCT) for extremity allows multi-energy high-resolution (HR) imaging for tissue characterization and material decomposition. However, both radiation dose and imaging speed need improvement for contrast-enhanced and other studies. Despite the success of deep learning methods for 2D few-view reconstruction, applying them to HR volumetric reconstruction of extremity scans for clinical diagnosis has been limited due to GPU memory constraints, training data scarcity, and domain gap issues. In this paper, we propose a deep learning-based approach for PCCT image reconstruction at halved dose and doubled speed in a New Zealand clinical trial. Particularly, we present a patch-based volumetric refinement network to alleviate the GPU memory limitation, train network with synthetic data, and use model-based iterative refinement to bridge the gap between synthetic and real-world data. The simulation and phantom experiments demonstrate consistently improved results under different acquisition conditions on both in- and off-domain structures using a fixed network. The image quality of 8 patients from the clinical trial are evaluated by three radiologists in comparison with the standard image reconstruction with a full-view dataset. It is shown that our proposed approach is essentially identical to or better than the clinical benchmark in terms of diagnostic image quality scores. Our approach has a great potential to improve the safety and efficiency of PCCT without compromising image quality.

Energy-discriminative performance of a spectral micro-CT system.

Experiments were performed to evaluate the energy-discriminative performance of a spectral (multi-energy) micro-CT system. The system, designed by MARS (Medipix All Resolution System) Bio-Imaging Ltd. (Christchurch, New Zealand), employs a photon-counting energy-discriminative detector technology developed by CERN (European Organization for Nuclear Research). We used the K-edge attenuation characteristics of some known materials to calibrate the detector's photon energy discrimination. For tomographic analysis, we used the compressed sensing (CS) based ordered-subset simultaneous algebraic reconstruction techniques (OS-SART) to reconstruct sample images, which is effective to reduce noise and suppress artifacts. Unlike conventional CT, the principal component analysis (PCA) method can be applied to extract and quantify additional attenuation information from a spectral CT dataset. Our results show that the spectral CT has a good energy-discriminative performance and provides more attenuation information than the conventional CT.

Ex-vivo atherosclerotic plaque characterization using spectral photon-counting CT: Comparing material quantification to histology.

BACKGROUND AND AIMS: Atherosclerotic plaques are characterized as being vulnerable to rupture based on a series of histologically defined features, including a lipid-rich necrotic core, spotty calcification and ulceration. Existing imaging modalities have limitations in their ability to distinguish between different materials and structural features. We examined whether X-ray spectral photon-counting computer tomography (SPCCT) images were able to distinguish key plaque features in a surgically excised specimen from the carotid artery with comparison to histological images. METHODS: An excised carotid plaque was imaged in the diagnostic X-ray energy range of 30-120 keV using a small-bore SPCCT scanner equipped with a Medipix3RX photon-counting spectral X-ray detector with a cadmium telluride (CdTe) sensor. Material identification and quantification (MIQ) images of the carotid plaque were generated using proprietary MIQ software at 0.09 mm volumetric pixels (voxels). The plaque was sectioned, stained and photographed at high resolution for comparison. RESULTS: A lipid-rich core with spotty calcification was identified in the MIQ images and confirmed by histology. MIQ showed a core region containing lipid, with a mean concentration of 260 mg lipid/ml corresponding to a mean value of -22HU. MIQ showed calcified regions with mean concentration of 41 mg Ca/ml corresponded to a mean value of 123HU. An ulceration of the carotid wall at the bifurcation was identified to be lipid-lined, with a small calcification identified near the breach of the artery wall. CONCLUSIONS: SPCCT derived material identification and quantification images showed hallmarks of vulnerable plaque including a lipid-rich necrotic core, spotty calcifications and ulcerations.

Dosimetry in MARS spectral CT: TOPAS Monte Carlo simulations and ion chamber measurements.

Spectral computed tomography (CT) is an up and coming imaging modality which shows great promise in revealing unique diagnostic information. Because this imaging modality is based on X-ray CT, it is of utmost importance to study the radiation dose aspects of its use. This study reports on the implementation and evaluation of a Monte Carlo simulation tool using TOPAS for estimating dose in a pre-clinical spectral CT scanner known as the MARS scanner. Simulated estimates were compared with measurements from an ionization chamber. For a typical MARS scan, TOPAS estimated for a 30 mm diameter cylindrical phantom a CT dose index (CTDI) of 29.7 mGy; CTDI was measured by ion chamber to within 3% of TOPAS estimates. Although further development is required, our investigation of TOPAS for estimating MARS scan dosimetry has shown its potential for further study of spectral scanning protocols and dose to scanned objects.

Bioremediation of pesticide contaminated water using an organophosphate degrading enzyme immobilized on nonwoven polyester textiles.

Bioremediation using enzymes has become an attractive approach for removing hazardous chemicals such as organophosphate pesticides from the environment. Enzymes immobilized on solid carriers are particularly suited for such applications. In this study, the organophosphate degrading enzyme A (OpdA) was covalently immobilized on highly porous nonwoven polyester fabrics for organophosphate pesticide degradation. The fabrics were first activated with ethylenediamine to introduce free amine groups, and the enzyme was then attached using the bifunctional crosslinker glutaraldehyde. The immobilization only slightly increased the Km (for methyl parathion, MP), broadened the pH profile such that the enzyme had significant activity at acidic pH, and enhanced the stability of the enzyme. The OpdA-functionalized fabrics could be stored in a phosphate buffer or in the dry state at 4°C for at least 4 weeks without a large loss of activity. When used in batch mode, the functionalized textiles could degrade 20 µM MP in un-buffered water at liquor to fabric ratios as high as 5000:1 within 2h, and could be used repeatedly. The fabrics could also be made into columns for continuous pesticide degradation. The columns were able to degrade 50 µM MP at high flow rates, and could be used repeatedly over 2 months. These results demonstrate that OpdA immobilized on nonwoven polyester fabrics is useful in environmental remediation of organophosphate compounds.