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1. TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, is reportedly excreted predominantly through urinary excretion in an unchanged form in humans, with partial biliary excretion also possible. However, the clearance mechanisms remain unclear. The aim of this study was to investigate the clearance mechanisms in humans and to assess species differences in the excretion routes.2. TP0463518 was not metabolised in rat, dog, or human hepatocytes. TP0463518 is a substrate for human BCRP, OATP1B1, OATP1B3, and OAT3, suggesting that renal uptake by OAT3 is probably the predominant clearance route, with hepatic uptake by OATP1B1 and OATP1B3 contributing partially to clearance in humans.3. A species difference in excretion routes was observed. The unchanged urinary excretion rates in humans, male rats, female rats, dogs, and monkeys were 80.7%, 0.1%, 40.9%, 15.2%, and 72.6%, respectively. Urinary excretion was predominant in humans and monkeys, while only biliary excretion was observed in male rats. Uptake studies using hepatocytes showed that the hepatic uptake clearance in rats was 13.6-fold higher than that in humans. Therefore, not only reabsorption

A convenient LC-MS/MS assay method to simultaneously and sensitively determine (R,S)-ketamine (Ket), (R,S)-norketamine (NK), and (2R,6R;2S,6S)-hydroxynorketamine (HNK) enantiomers in plasma and brain from mice was developed. This method enables the chiral separations of these six enantiomers in one analysis by constructing a column-switching system composed of one achiral column and two chiral columns with a relatively short analysis time (17 min). The chromatography involves the separation of (2R,6R;2S,6S)-HNK from (R,S)-Ket and (R,S)-NK on an octadecyl-silica column, followed by chiral separations on a CHIRALPAK AY-RH column for (2R,6R;2S,6S)-HNK or on a CHIRALPAK AS-RH column for the other analytes. The calibration curves for plasma and brain showed a good linearity in the range of 3-1000 ng/mL and 1.5-500 ng/g, respectively. The accuracy ranged from 90.0% to 104.0% in within-run and between-run. This validated method was applicable to determine the stereoselective pharmacokinetic profiles of (R,S)-Ket, (R,S)-NK, and (2R,6R;2S,6S)-HNK in plasma and brain collected from individual mice after a single intraperitoneal dosing of racemic Ket at an antidepressant dose. It is hoped that this assay will greatly help for understanding the relationship between the antidepressant actions of (R,S)-Ket enantiomers or their metabolites and their pharmacokinetics.

For ester prodrugs that are used to improve the gastrointestinal absorption of highly hydrophilic, pharmacologically active substances, it is challenging to predict the human pharmacokinetics (PK) of the prodrugs and their parent compounds using only preclinical data.This research was aimed at constructing a PBPK model for predicting the human PK of the ester prodrug MGS0274 and its parent compound MGS0008 after a single oral administration of MGS0274 besylate.First, we identified carboxylesterase 1 (CES1) as the major enzyme involved in the hydrolysis of MGS0274. Second, we constructed a new compartment model to estimate the passive diffusion clearance (CLpd) of MGS0008, a critical parameter for predicting the PK of highly hydrophilic compounds, based on in vivo monkey PK data. Finally, we constructed a permeability-limited liver PBPK model incorporating the CLpd assumed to be the same in humans.We confirmed that our method reliably predicted the human PK and that the estimated CLpd was comparable to that calculated retrospectively using the PBPK model, suggesting that the methodology for estimating the CLpd was valid.Our proposed methodology is expected to be helpful for human PK prediction of ester prodrugs hydrolysed by CES1 and their hydrophilic parent compounds even during the preclinical phase. For ester prodrugs that are used to improve the gastrointestinal absorption of highly hydrophilic, pharmacologically active substances, it is challenging to predict the human pharmacokinetics (PK) of the prodrugs and their parent compounds using only preclinical data. This research was aimed at constructing a PBPK model for predicting the human PK of the ester prodrug MGS0274 and its parent compound MGS0008 after a single oral administration of MGS0274 besylate. First, we identified carboxylesterase 1 (CES1) as the major enzyme involved in the hydrolysis of MGS0274. Second, we constructed a new compartment model to estimate the passive diffusion clearance (CLpd) of MGS0008, a critical parameter for predicting the PK of highly hydrophilic compounds, based on in vivo monkey PK data. Finally, we constructed a permeability-limited liver PBPK model incorporating the CLpd assumed to be the same in humans. We confirmed that our method reliably predicted the human PK and that the estimated CLpd was comparable to that calculated retrospectively using the PBPK model, suggesting that the methodology for estimating the CLpd was valid. Our proposed methodology is expected to be helpful for human PK prediction of ester prodrugs hydrolysed by CES1 and their hydrophilic parent compounds even during the preclinical phase.

In order to produce versatile and potentially functional terpene-based compounds, a (R)-limonene-derived diol and its corresponding five-membered cyclic carbonate were prepared. The diol (cyclic carbonate) comprises four diastereomers based on the stereochemical configuration of the diol (and cyclic carbonate) moiety. By choosing the appropriate starting compounds (trans- and cis-limonene oxide) and conditions, the desired diastereomers were synthesised in moderate to high yields with, in most cases, high stereoselectivity. Comparison of the NMR data of the obtained diols and carbonates revealed that the four different diastereomers of each compound could be distinguished by reference to their characteristic signals.

Drug-induced phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of tissue phospholipids. Although azithromycin can be used to induce phospholipidosis, no experimental studies evaluating the relationship between drug accumulation and phospholipid localization have been performed. In this study, azithromycin was orally administered to rats for 7 days, and the relationship between drug and phospholipid accumulation was performed using imaging mass microscopy. The administration of azithromycin induced tubular epithelial vacuolation in the inner stripe of the outer medulla of the kidney, consistent with the lamellar bodies that are typical manifestations of drug-induced phospholipidosis. Azithromycin and phospholipid tissue levels were extensively elevated in the kidneys of azithromycin-treated rats. Imaging mass microscopy revealed that both azithromycin and its metabolites were found in the kidneys of azithromycin-treated rats but not in control animals. The vacuolated areas of the kidneys were primarily found in the inner stripe of the outer medulla, consistent with the areas of high azithromycin concentration. Azithromycin was colocalized with several phospholipids-phosphatidylinositol (18:0/20:4), phosphatidylethanolamine (18:0/20:4 and 16:0/20:4), and possibly didocosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate, a putative biomarker of drug-induced phospholipidosis. In summary, we found correlations between regions of kidney damage and the accumulation of azithromycin, its metabolites, and phospholipids using imaging mass microscopy. Such analyses may help reveal the mechanism and identify putative biomarkers of drug-induced phospholipidosis.

A series of experiments was conducted in order to measure the maximum heat release rate of a wood crib ignited at the center of its base after water applications which were not sufficient to extinguish the wood crib fire. The novelty of the present experiments lies in distributing the water uniformly just above the top surface thus ensuring what the exact delivery density is. Uniform water distribution was produced by a system of pipes with holes 5 cm above the wood crib. The variable experimental parameters were the number of layers of wood cribs (6, 9, 12), the water delivered density, and the water activation time. The size of the wood sticks is fixed and they are layered in a fixed staggered way alternating at 9 or 10 sticks per layer. Regardless of the number of wood crib layers, the reduction of the maximum heat release rate by water supplication was proportional to the total water flow rate W ˙ . The constant of proportionality is approximately 12 kJ/g in these experiments for all water delivered densities and all numbers of layers of wood cribs where water was applied either earlier or just when the maximum heat release rate was reached in the free burning wood crib fires. The proportionality factor 12 kJ/g is explained by noting that the heat removed per unit time by the completely evaporated water is proportional to the water application rate times the heat of evaporation and that this leads to the reduction of mass loss rate to be proportional to the water application rate multiplied by the heat of evaporation and divided by the heat of pyrolysis of wood. Therefore, the reduction of heat release rate is equal to the reduction of the mass loss rate multiplied by the heat of combustion of wood. In addition, data for the total heat released and the total mass loss also support the proposition that the reduction in the total heat release is due to the extinction of the wood crib burning area being proportional to the water supply rate. We expect that these results to be applicable as long as the burning of wood crib is fuel controlled.

In amendment of Building Standards Act of the year 2000, the verification method for evacuation safety was introduced. Knowledge gained in Togawa’s study (1955) is frequently used in this verification method; however, depending on the spatial condition, the estimated results differ from the actual crowd walk nature and this remains a challenge. Considering the situation, this study aims to illustrate the relationship between the spatial condition and crowd walk nature and analyze data gained from the Crowd Evacuation Experiment done in 2015 at Tokyo University of Science. When a corridor includes an opening (a bottleneck) or a merging, a pedestrian crowd will be restrained at the opening/merging. Each part of the bottleneck corridor showed a very similar feature as the merging corridor. Therefore, this study analyzed the bottleneck corridor and merging corridor with a uniform model. These analysis results confirmed the relationship between each part’s density and the ratio of inflow width to the outflow width and showed that specific flow can be calculated from the margin of two densities, regardless of the spatial condition.

The rapid-acting and long-lasting antidepressant effects of (R,S)-ketamine have recently gained much attention. Although (S)-ketamine has been studied as an active isomer, recent evidence suggests that (R)-ketamine exhibits longer-lasting antidepressant effects than (S)-ketamine in rodents. However, the antidepressant potential of (R)-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-ketamine with those of (S)-ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-ketamine and (S)-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, (R)-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of (S)-ketamine was no longer observed. Moreover, (R)-ketamine, but not (S)-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-ketamine and (S)-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (

Treatment of an ynone-bearing azulene with tertiary amines resulted in transformation of the corresponding enaminone in high yield. The product ratio depended on the group at the structure of the amine. Investigation of the reaction mechanism indicated that treatment of the ynone with a tertiary amine gave the corresponding ammonium salt, followed by removal of an alkyl group to form the enaminone as the final product. The color of the enaminone was different than that of the ynone.

Two diastereomers of d-limonene-derived five-membered cyclic carbonates were prepared from the corresponding isomers of d-limonene oxide with CO2. Their syntheses were catalyzed by commercially available tetrabutylammonium chloride with high stereoselectivity. The reaction behavior dependent on the reaction conditions such as CO2 pressure was clarified.

The reduction of various hydantoins with sodium borohydride gave the corresponding 4-hydroxy- 2-imidazolidinones in high yields. In contrast, reduction employing a boron trifluoride etherate-sodium borohydride system generated 2-imidazolidinones. In both reductions, the reactivity of the hydantoin was dependent on its substituents. The Lewis acid-promoted reactions of a 4-hydroxy-2-imidazolidinone with nucleophiles were also investigated.

Knowledge about the mass flow rate of a ceiling jet in a large space is important for predicting smoke behavior, determining suitable smoke control equipment, and designing the operating conditions in the early stages of a fire. Here, full-scale ceiling jet tests with a flat unconfined ceiling were conducted. The mass flow rate of a ceiling jet spreading in the radial direction was estimated based on measurement of carbon dioxide concentration. The relation between the entrainment properties of the ceiling jet and radial distance was experimentally investigated. Empirical formulae representing the dependence of the carbon dioxide concentration decrease with radial distance was developed. The entrainment coefficient characteristic by ceiling jet was also described.

A cleavage reaction of 1-acylhydantoin by an amine in tetrahydrofuran at elevated temperature provided the corre-sponding amide and hydantoin in high yield. It was found that the addition of diethylaluminum chloride accelerated the cleavage reaction rate. The amide yield depended on the steric hindrance of the amine.

The rapid-acting and long-lasting antidepressant effects of (

In this research, a full-scale fire experiment was conducted for the purpose of estimating the influence of differences in air supply systems on smoke shielding performance in air pressure smoke control. As a result, the following items were indicated by the experiment: 1. As smoke invades from the doorway surface even prior to the smoke shield limit time in cases where smoke shield opening door is intermediately open as generally considered in the field of air pressure smoke control, smoke shields require thrust from two orthogonal surfaces with each other. 2. In static pressure systems, smoke shielding performance is fixed in spite of the smoke shield opening door angle, and previous theoretical formulae often coincide with actual values. 3. In dynamic pressure systems, smoke shielding performance differs depending on the air supply system and the angles of the door of the smoke shield opening. There are systems where smoke shielding performance is better than in static pressure systems, and there are also systems where it is worse.

To evaluate the importance of fire protection systems objectively in evacuation safety planning of building fires, authors have proposed a methodology for selecting both design fire scenarios and design fire simultaneously for performance-based fire safety design according to acceptable evacuation risk in fire, which we call risk-based evacuation safety design method or R-B ESDM in abbreviated term. An important factor when using the R-B ESDM is to set the reliability of sprinkler systems. Although several studies exist on the reliability of sprinkler systems, there is no study that looks into the relations of design fire and design fire scenarios. In order to introduce the reliability of sprinkler systems to R-B ESDM, the data of the national fire reports have been statistically analyzed by classifying the fires in the sprinklered spaces into three patterns: “fires that sprinklers extinguished,” “fires that sprinklers suppressed,” and “fires that sprinklers failed to control.” The probabilities of the three patterns have been calculated by using the number of fires according to the burned area. As a result, if the burned area for effective suppression is defined as less than 4 m2, the reliability of effective sprinkler activation turns out to be approximately 83 %.