Evaluation of the extracranial "multifocal arcuate sign," a novel MRI finding for the diagnosis of giant cell arteritis, on STIR and contrast-enhanced T1-weighted images.

BACKGROUND: While early diagnosis of giant cell arteritis (GCA) based on clinical criteria and contrast-enhanced MRI findings can lead to early treatment and prevention of blindness and cerebrovascular accidents, previously reported diagnostic methods which utilize contrast-enhanced whole head images are cumbersome. Diagnostic delay is common as patients may not be aware of initial symptoms and their significance. To improve current diagnostic capabilities, new MRI-based diagnostic criteria need to be established. This study aimed to evaluate the "multifocal arcuate sign" on short tau inversion recovery (STIR) and contrast-enhanced T1-weighted (CE-T1W) images as a novel extracranial finding for the diagnosis of GCA. METHODS: A total of 17 consecutive patients (including five with GCA) who underwent CE-T1W and whole-brain axial STIR imaging simultaneously between June 2010 and April 2020 were enrolled. We retrospectively reviewed their MR images. The "multifocal arcuate sign" was defined as "multiple distant arcuate areas with high signal intensity in extracranial soft tissues such as subcutaneous fat, muscles, and tendons." Extracranial abnormal high-signal-intensity areas were classified as "None," when no lesions were detected; "Monofocal," when lesions were detected only in one place; and "Multifocal," when lesions were detected in multiple places. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of "Multifocal" areas were calculated using cross tabulation. Fisher's exact test was used to compare "Multifocal" areas in five patients with GCA and those with other diseases. In addition, mean Cohen's kappa and Fleiss' kappa statistics were used to compare inter-reader agreement. RESULTS: The sensitivity, specificity, PPV, and NPV of the "multifocal arcuate sign" in patients with GCA were 60%, 92-100%, 75-100%, and 85-86%, respectively. Significantly more patients with GCA had "Multifocal" areas compared to those with other diseases (Fisher's exact test, p = 0.008-0.027). Mean Cohen's kappa and Fleiss' kappa for inter-reader agreement with respect to the five GCA patients were 0.52 and 0.49, respectively, for both STIR and CE-T1W sequences. CONCLUSIONS: The new radiologic finding of "multifocal arcuate sign" on STIR and CE-T1W images may be used as a radiologic criterion for the diagnosis of GCA, which can make plain MRI a promising diagnostic modality.

Design of closed loop for reproduction of gas-dominated hydrate flow.

The study presents a novel setup for measuring the flow regime of hydrate particles in a gas-dominated flow, which is of interest for applications such as natural gas transportation. A closed-flow loop, driven by a novel internal fan, enables continuous observation of hydrate particle behavior in a gas flow. The experimental setup allows the production and insertion of HFC134a gas hydrate particles with diameters of 10-50 µm into the gas flow loop via a bypass loop. The performance curve of the internal fan is validated, and its suitability for achieving the required flow speed (5 m/s) is demonstrated. Through an observation window using camera systems, the flow regime of glass beads is successfully visualized and analyzed. To validate the experimental data, a coupled computational fluid dynamics-discrete element method model is used to simulate the particle flow density distribution. The study findings demonstrate the effectiveness of the experimental setup in characterizing the flow regime of hydrate particles in a gas-dominated flow.

Preclinical metabolism and the disposition of vornorexant/TS-142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia.

We investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [14 C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug-derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24 h post-dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next-day residual effects in humans.

Pharmacokinetics, pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized, double-blind, placebo-controlled phase-1 studies.

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double-blind studies: a single ascending dose of 1-30 mg (Study 101; n = 6) and multiple ascending doses of 10-30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open-label, 20 mg repeated-dose in non-elderly individuals (Step 1; n = 12) and a double-blind, 20 mg repeated-dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500-3.00 h (range) and elimination half-life of 1.32-3.25 h. The area under the plasma concentration-time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness-related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post-dose, whereas no consistent dose-related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC0-inf . Exposure in elderly individuals was generally comparable to that in non-elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next-day residual effects.

A retrospective preliminary study of intrapancreatic late enhancement as a noteworthy imaging finding in the early stages of pancreatic adenocarcinoma.

OBJECTIVE: To characterize intrapancreatic late enhancement (ILE) observed in the early stages of pancreatic adenocarcinoma (PAC). METHODS: Among 203 patients pathologically diagnosed with PAC between October 2011 and February 2021, 32 patients with pre-diagnostic abdominal contrast-enhanced CT performed from 6 months to 5 years before the diagnosis were enrolled in this study. Indirect findings (IFs) on pre-diagnostic CT, including ILE, were evaluated and examined for various clinical data and time intervals to diagnosis (TIDs). The detected ILE was quantitatively evaluated, and the effect of ILE awareness on lesion detection by two radiologists and their interobserver agreement were assessed. RESULTS: Among the 32 patients, 23 showed IFs. ILE was observed in 14 patients (63%), with a median TID of 17 months (interquartile ratio [IQR]: 9.3-42.3). ILE alone was observed in eight patients (35%), ILE with focal pancreatic parenchymal atrophy (FPPA) was observed in five patients (22%), and ILE with main pancreatic duct abnormalities (MPDA) was observed in one patient (4%). Pancreatic head lesions were significantly more frequent in patients with ILE alone than in patients with FPPA or MPDA (p = 0.026). The median long-axis diameters of the region with ILE and ILE-to-pancreas contrast were 10 (IQR: 5-11) mm and 24 (IQR: 17-33) HU, respectively. Awareness of ILE led observers to detect two or three more pancreatic head lesions, and interobserver agreement increased from poor agreement (k = 0.17) to moderate agreement (k = 0.55). CONCLUSION: ILE is a significant IF for early PAC detection. KEY POINTS: • Intrapancreatic late enhancement (ILE) is a significant indirect finding in the early detection of pancreatic adenocarcinoma. • ILE without other indirect findings is expected to help detect pancreatic head lesions. • Image evaluation focusing on ILE can increase lesion detection and improve the interobserver agreement.

Pancreatic perfusion imaging method that reduces radiation dose and maintains image quality by combining volumetric perfusion CT with multiphasic contrast enhanced-CT.

OBJECTIVES: The aim of this study is to propose and evaluate a new method of volumetric perfusion computed tomography (PCT) incorporated into pancreatic multiphasic contrast enhanced (CE)-CT in the clinical setting. METHODS: In this ethically approved study, PCT was incorporated into our existing scanning protocol in 17 patients and effective doses related to PCT were evaluated. CT values and signal-to-noise ratio (SNR) of anatomical structure were compared in diagnostic images that were acquired using 320-detector volumetric scan mode and 64-detector helical scan mode. In addition, focal lesion depiction was qualitatively assessed in the two groups. Perfusion parameters in normal pancreas were measured by two radiologists and the interobserver-reliability was assessed. RESULTS: The effective dose of PCT was 5.1 ± 0.3 mSv. The actual effective dose (AED) including the dose used in volumetric scans for diagnostic imaging was 22.8 ± 5.3 mSv and the putative effective dose (PED) was 21.9 ± 9.1 mSv on average. There was no significant difference between AED and PED (p = 0.404). Compared with conventional helical scans, volumetric scans did not decrease CT values or SNR, but rather significantly increased those of the aorta in the arterial phase. Both groups had acceptable qualitatively assessed image quality with no significant difference in the depiction of each structure. There was almost perfect interobserver agreement in the measurement of perfusion parameters (mean ICCs > 0.9). CONCLUSIONS: Our scanning protocol for pancreatic perfusion CT provides high-quality images while requiring lower radiation doses than conventional methods.

Clinical and image features: large-vessel vasculitis after granulocyte colony stimulating factor administration.

BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is known to cause vasculitis, mainly in the small vessels. Several cases of large-vessel vasculitis (LVV) caused by G-CSF have recently been reported in the literature; we retrospectively suspect that some cases of LVV in our institution were associated with administration of G-CSF. PURPOSE: To evaluate the clinical and radiological findings in our cases and to compare them with those in previous reports. MATERIAL AND METHODS: We retrospectively evaluated clinical and radiological findings in four cases of LVV that occurred after administration of G-CSF in our institution. We also reviewed papers on G-CSF-related LVV and compared their findings to ours. RESULTS: G-CSF-related LVV occurred in patients aged > 50 years and more frequently in women. Most patients developed vasculitis within 15 days after the last administration. While 14/16 patients were symptomatic, the remaining two patients were asymptomatic and diagnosed incidentally. In all cases, laboratory inflammatory markers increased, but there were no autoantibodies that clearly indicated other autoimmune vasculitis. Computed tomography revealed elevated soft tissue density around the affected vessels. CONCLUSION: LVV is among the potential adverse events of G-CSF administration. We should keep this outcome in mind when we interpret medical images of patients with previous G-CSF treatment history even if they are asymptomatic.

KCNQ1 is internalized by activation of α1 adrenergic receptors.

KCNQ1 (Kv7.1 or KvLQT1) plays important physiological roles in various tissues forming potassium channels with KCNE subunits. Among the channels formed by KCNQ1 and KCNE subunits, the best studied is the slow delayed rectifier potassium channel in the heart, the IKs (KCNQ1/KCNE1) channel, which is critical for repolarization of cardiac action potential. The KCNQ1 channel is internalized by Nedd4/Nedd4-like ligase-dependent ubiquitination. It is also reported that phosphorylation of KCNE1 by PKC results in internalization of the KCNQ1/KCNE1 channel. Because we have observed down-regulation of KCNQ1/KCNE1 currents by activation of the α1-adrenergic receptor (α1AR) that activates PKC, this study investigated whether α1AR causes internalization of the KCNQ1 protein. We fused HaloTag to the extracellular region of KCNQ1 (Halo-KCNQ1) and co-expressed it with α1ARs in HEK293 cells. The KCNQ1 protein on the cell surface was selectively labeled with membrane-impermeable HaloTag ligands, and changes in its localization were monitored by confocal fluorescence microscopy. Activation of α1AAR and α1BAR caused marked internalization of KCNQ1, which was not KCNE1-dependent. Internalization of KCNQ1 by α1AR activation was inhibited by disruption of the PY motif or the YXXΦ motif in the C-terminus. Double staining for the receptor and the channel revealed that KCNQ1 internalization was independent of α1AR internalization. Our results suggest that α1AR-mediated direct internalization of KCNQ1 is AP2/clathrin-dependent and may be triggered by ubiquitination of KCNQ1 via the AMP dependent kinase (AMPK)/Nedd4-2 pathway. When phenylephrine was applied to rat neonatal cardiomyocytes transfected with KCNQ1 and α1AR, the KCNQ1 protein was internalized. The internalization of KCNQ1 by α1AR would affect pathophysiology in a variety of tissues expressing KCNQ1, which merits further in vivo study.

Prediction of human percutaneous absorption from in vitro and in vivo animal experiments.

Although anatomical and structural similarities between the skin of minipigs and humans are often reported, few percutaneous pharmacokinetic studies have been conducted in minipigs. The objective of this study was to clarify the usefulness of minipigs for estimating the percutaneous absorption of various drugs in humans. The absorption of several marketed drugs was observed in mice, rats and minipigs both in vivo and in vitro, and results were compared with those in humans. For all six model drugs, after percutaneous administration in vivo, fraction of dose absorbed (F) from the skin was the lowest in minipigs among the four species studied, including humans. In vitro drug permeation results were similar, with the lowest permeability observed in minipigs. However, combined use of both in vitro permeation and in vivo absorption data from minipigs using triple pack approach resulted in better prediction of human F values than data obtained from mice. These results suggest some qualitative, but not quantitative, similarities between the drug absorption process across the skin of minipigs and humans. In conclusion, minipigs appear to be a promising model animal for predicting percutaneous drug absorption in humans, however, more in vivo and in vitro studies are needed to improve predictability.

[CEREBRAL VENOUS SINUS THROMBOSIS IN PATIENTS WITH METASTATIC TESTICULAR CANCER DURING CHEMOTHERAPY: REPORTS OF TWO CASES].

Cerebral venous sinus thrombosis (CVT) is rare but sometimes develops in association with malignant neoplasm. We report two cases of CVT that occurred during cisplatin-based chemotherapy for testicular cancer. A 46-year-old man with stage IIA non-seminomatous germ cell tumour was treated with conventional doses of etoposide and cisplatin (EP). On day 11 of the third treatment course, he developed a systemic seizure. Brain computed tomography (CT) and magnetic resonance (MR) imaging could not detect the cause. Enhanced chest-pelvic CT revealed pelvic thrombosis. Administration of phenytoin for epilepsy of unknown cause and heparin for thrombosis was started. He had completed 4 courses of EP therapy without seizure recurrence. After re-evaluating the brain CT images retrospectively, we found high density of superior sagittal sinus (SSS) and strongly suspected CVT. Another patient was a 47-year-old man with stage IIIB seminomatous germ cell tumour treated with bleomycin, etoposide, and cisplatin (BEP) therapy. On day 11 of the second treatment course, he developed a systemic seizure. Brain CT revealed subarachnoid haemorrhage localised in the right parietal lobe. CT venography revealed a filling defect in the superior sagittal sinus (SSS). MR venography revealed a SSS stenosis. We diagnosed the cause of the seizure as CVT and started administration of anticoagulant therapy. After the thrombus had diminished, chemotherapy was restarted and another 2 courses of BEP therapy was completed.

A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk.

The approach for predicting the degree of drug-induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. Thirty-eight drugs were classified by DILI risk into five categories based on drug labels approved by the Food and Drug Administration (FDA) as follows: withdrawn (WDN), boxed warning (BW), warnings and precautions (WP), adverse reactions (AR), and no match (NM). Also, WP was classified into two categories: high and low concern. Differentiated HepaRG cells were treated with drugs for 24 h. The maximum concentration was set at 100-fold the therapeutic maximum plasma concentration (Cmax ). After treatment with drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. As modified cut-off values of each parameter, the TC50 (toxic concentration that decreased the response by 50%) and EC200 (effective concentration giving a response equal to 200% of controls) were calculated. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. This modified multiparametric assay showed an 87% sensitivity and 87% specificity for predicting the DILI risk. The toxicity score showed a good predictive performance for WDN, BW and WP (high concern) categories [cut-off: score ≥ 1; area under a receiver operating characteristic curve (ROC-AUC): 0.88], and for WDN and BW categories (cut-off: score ≥ 3; ROC-AUC: 0.88). This study newly indicated that the degree of DILI risk might be predictable quantitatively by assessing the toxicity score in the modified multiparametric assay using HepaRG cells. Copyright © 2016 John Wiley & Sons, Ltd.

Efficacy Coefficients Determined Using Nail Permeability and Antifungal Activity in Keratin-Containing Media Are Useful for Predicting Clinical Efficacies of Topical Drugs for Onychomycosis.

Onychomycosis is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. In order to obtain an in vitro index that is relevant to the clinical efficacy of topical anti-onychomycosis drugs, we profiled five topical drugs: amorolfine, ciclopirox, efinaconazole, luliconazole, and terbinafine, for their nail permeabilities, keratin affinities, and anti-dermatophytic activities in the presence of keratin. Efinaconazole and ciclopirox permeated full-thickness human nails more deeply than luliconazole. Amorolfine and terbinafine did not show any detectable permeation. The free-drug concentration of efinaconazole in a 5% human nail keratin suspension was 24.9%, which was significantly higher than those of the other drugs (1.1-3.9%). Additionally, efinaconazole was released from human nail keratin at a greater proportion than the other drugs. The MICs of the five drugs for Trichophyton rubrum were determined at various concentrations of keratin (0-20%) in RPMI 1640 medium. The MICs of ciclopirox were not affected by keratin, whereas those of efinaconazole were slightly increased and those of luliconazole and terbinafine were markedly increased in the presence of 20% keratin. Efficacy coefficients were calculated using the nail permeation flux and MIC in media without or with keratin. Efinaconazole showed the highest efficacy coefficient, which was determined using MIC in media with keratin. The order of efficacy coefficients determined using MIC in keratin-containing media rather than keratin-free media was consistent with that of complete cure rates in previously reported clinical trials. The present study revealed that efficacy coefficients determined using MIC in keratin-containing media are useful for predicting the clinical efficacies of topical drugs. In order to be more effective, topical drugs have to possess higher efficacy coefficients.

Establishment of In Silico Prediction Models for CYP3A4 and CYP2B6 Induction in Human Hepatocytes by Multiple Regression Analysis Using Azole Compounds.

Drug-drug interactions (DDIs) via cytochrome P450 (P450) induction are one clinical problem leading to increased risk of adverse effects and the need for dosage adjustments and additional therapeutic monitoring. In silico models for predicting P450 induction are useful for avoiding DDI risk. In this study, we have established regression models for CYP3A4 and CYP2B6 induction in human hepatocytes using several physicochemical parameters for a set of azole compounds with different P450 induction as characteristics as model compounds. To obtain a well-correlated regression model, the compounds for CYP3A4 or CYP2B6 induction were independently selected from the tested azole compounds using principal component analysis with fold-induction data. Both of the multiple linear regression models obtained for CYP3A4 and CYP2B6 induction are represented by different sets of physicochemical parameters. The adjusted coefficients of determination for these models were of 0.8 and 0.9, respectively. The fold-induction of the validation compounds, another set of 12 azole-containing compounds, were predicted within twofold limits for both CYP3A4 and CYP2B6. The concordance for the prediction of CYP3A4 induction was 87% with another validation set, 23 marketed drugs. However, the prediction of CYP2B6 induction tended to be overestimated for these marketed drugs. The regression models show that lipophilicity mostly contributes to CYP3A4 induction, whereas not only the lipophilicity but also the molecular polarity is important for CYP2B6 induction. Our regression models, especially that for CYP3A4 induction, might provide useful methods to avoid potent CYP3A4 or CYP2B6 inducers during the lead optimization stage without performing induction assays in human hepatocytes.

Usefulness of minipigs for predicting human pharmacokinetics: Prediction of distribution volume and plasma clearance.

In this study, advantages of minipigs to use in preclinical study for new drug development were evaluated in terms of prediction of human pharmacokinetic (PK) parameters of various drugs. Fourteen model drugs having diverse physicochemical properties were selected and intravenously administered to mice, rats and minipigs to obtain their PK parameters. The human volume of distribution (Vd) and clearance (CL) of model drugs were predicted from PK parameters in each animal species. When Vd of 14 drugs in each species were directly compared with those in humans, minipigs showed the highest correlation. Correction of Vd with an unbound fraction of drugs in tissues further improved the correlation. Allometric scaling that included minipig data resulted in high accuracy in the prediction of human Vd, clearly indicating an importance of minipig data. Minipigs also showed the high predictability of human CL. The prediction of human CL by allometric scaling showed a high accuracy when the data of minipigs were included. In conclusion, potential advantages of minipigs for predicting human Vd and CL were clearly demonstrated. Reliable prediction of human PK from data of minipigs appears to be possible in preclinical PK study, without relying on PK analysis in other species.

Detectability and anatomical correlation of middle ear cholesteatoma using fused thin slice non-echo planar imaging diffusion-weighted image and magnetic resonance cisternography (FTS-nEPID).

Cholesteatomas show high intensity in diffusion-weighted imaging (DWI). We performed fused thin slice non-echo planar imaging (EPI) DWI and magnetic resonance cisternography (FTS-nEPID) for cholesteatoma patients to increase the detectability of FTS-nEPID for cholesteatoma. The subjects are 77 consecutive patients who underwent FTS-nEPID as a preoperative study (mean age: 53.3±21.8, 47 men and 30 women). Otorhinolaryngologists performed the operations. We anatomically classified the middle ear into four portions. A radiologist evaluated the images for cholesteatoma and assessed the anatomical invasive range in four portions using only FTS-nEPID. We classified large cholesteatomas that invaded more than three portions and small ones that invaded less than two portions based on the results obtained from surgery, and calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). For all cholesteatomas with an existing diagnosis, the sensitivity, specificity, PPV, and NPV were 71%, 70%, 94%, and 27%, respectively. In anatomical evaluation, the sensitivity, specificity, PPV, and NPV were 49%, 85%, 77%, and 64%, respectively. For large cholesteatomas with an existing diagnosis, the sensitivity was 86%. In anatomical evaluation, the sensitivity, specificity, PPV, and NPV were 51%, 57%, 88%, and 18%, respectively. For small cholesteatomas with an existing diagnosis, the sensitivity, specificity, PPV, and NPV were 59%, 78%, 92%, and 30%, respectively. In anatomical evaluation, the sensitivity, specificity, PPV, and NPV were 40%, 85%, 60%, and 71%, respectively. FTS-nEPID may be useful for diagnosing cholesteatomas. Further research is needed for anatomical evaluation because there were many false-negative results.

Multiparametric assay using HepaRG cells for predicting drug-induced liver injury.

The utility of HepaRG cells as an in vitro cell-based assay system for assessing drug-induced liver injury (DILI) risk was investigated. Seventeen DILI-positive and 15 DILI-negative drugs were selected for the assay. HepaRG cells were treated with each drug for 24h at concentrations that were 1.6-, 6.3-, 25-, and 100-fold the therapeutic maximum plasma concentration (Cmax). After treatment, the cell viability, glutathione content, caspase 3/7 activity, lipid accumulation, leakage of lactate dehydrogenase, and albumin secretion were measured. The sensitivity and specificity were calculated to assess the ability of the assay to predict DILI. Our multiparametric assay using HepaRG cells exhibited a 67% sensitivity and 73% specificity at a 100-fold concentration of Cmax and a 41% sensitivity and 87% specificity at a 25-fold concentration of Cmax. When a 25-fold Cmax cut-off was applied, approximately 70% of drugs exhibiting positive responses were classified into the high DILI risk category. HepaRG cells distinguished relatively safe drugs from their high-risk analogs. Our study indicates that HepaRG cells may be of use to (1) prioritize drug analogs, (2) analyze the mechanism of DILI, and (3) assess the risk for DILI in the early drug discovery stage.

Quantitative assessment of intestinal first-pass metabolism of oral drugs using portal-vein cannulated rats.

PURPOSE: To evaluate the impact of intestinal first-pass metabolism (Fg) by cytochrome P4503A (CYP3A) and uridine 5'-diphosphate-glucuronosyltransferases (UGT) on in vivo oral absorption of their substrate drugs. METHODS: CYP3A and UGT substrates were orally administered to portal-vein cannulated (PV) rats to evaluate their intestinal availability (Fa · Fg). In the case of CYP3A substrates, vehicle or 1-aminobenzotriazole (ABT), a potent inhibitor of CYP enzymes, was pretreated to assess Fg separately from Fa (Enzyme-inhibition method). On the other hand, since potent inhibitors of UGT have not been identified, Fg of UGT substrate was calculated from total amount of metabolites generated in enterocytes (Metabolite-distribution method). RESULTS: After oral administration of CYP3A substrates in ABT-pretreated rats, the portal and systemic plasma concentrations of the metabolite were nearly the same, indicating almost complete inhibition of intestinal CYP3A-mediated metabolism. Using Enzyme-inhibition method, Fg of midazolam (1 mg/kg) was calculated as 0.71. Additionally, total amount of raloxifene-6-glucuronide generated in enterocytes after oral administration of raloxifene was estimated using Metabolite-distribution method and Fg of raloxifene (0.98 µmol/kg) was calculated as 0.21. CONCLUSIONS: PV rats enabled in vivo quantitative assessment of intestinal first-pass metabolism by CYP3A and UGT. This method is useful for clarifying the cause of low bioavailability.

Pressurized subsampling system for pressured gas-hydrate-bearing sediment: microscale imaging using X-ray computed tomography.

A pressurized subsampling system was developed for pressured gas hydrate (GH)-bearing sediments, which have been stored under pressure. The system subsamples small amounts of GH sediments from cores (approximately 50 mm in diameter and 300 mm in height) without pressure release to atmospheric conditions. The maximum size of the subsamples is 12.5 mm in diameter and 20 mm in height. Moreover, our system transfers the subsample into a pressure vessel, and seals the pressure vessel by screwing in a plug under hydraulic pressure conditions. In this study, we demonstrated pressurized subsampling from artificial xenon-hydrate sediments and nondestructive microscale imaging of the subsample, using a microfocus X-ray computed tomography (CT) system. In addition, we estimated porosity and hydrate saturation from two-dimensional X-ray CT images of the subsamples.

Clinical significance of mammillary body enhancement in Wernicke encephalopathy: report of 2 cases and review of the literature.

In 2 cases of Wernicke encephalopathy in which the initial symptom was double vision, the only abnormal finding on magnetic resonance (MR) imaging was abnormal enhancement of the mammillary bodies. The mammillary bodies are the region most vulnerable to abnormal enhancement. Because MR imaging with contrast enhancement can detect such abnormal enhancement at an early stage, it should be performed more often in patients with oculomotor disorders to avoid underdiagnosis of Wernicke encephalopathy.

Multiple-pressure-tapped core holder combined with X-ray computed tomography scanning for gas-water permeability measurements of methane-hydrate-bearing sediments.

We present a novel setup for measuring the effective gas-water permeability of methane-hydrate-bearing sediments. We developed a core holder with multiple pressure taps for measuring the pressure gradient of the gas and water phases. The gas-water flooding process was simultaneously detected using an X-ray computed tomography scanner. We successfully measured the effective gas-water permeability of an artificial sandy core with methane hydrate during the gas-water flooding test.