When to consider intra-target microdosing: physiologically based pharmacokinetic modeling approach to quantitatively identify key factors for observing target engagement

Intra-Target Microdosing (ITM), integral to Phase 0 clinical studies, offers a novel approach in drug development, effectively bridging the gap between preclinical and clinical phases. This methodology is especially relevant in streamlining early drug development stages. Our research utilized a Physiologically Based Pharmacokinetic (PBPK) model and Monte Carlo simulations to examine factors influencing the effectiveness of ITM in achieving target engagement. The study revealed that ITM is capable of engaging targets at levels akin to systemically administered therapeutic doses for specific compounds. However, we also observed a notable decrease in the probability of success when the predicted therapeutic dose exceeds 10 mg. Additionally, our findings identified several critical factors affecting the success of ITM. These encompass both lower dissociation constants, higher systemic clearance and an optimum abundance of receptors in the target organ. Target tissues characterized by relatively low blood flow rates and high drug clearance capacities were deemed more conducive to successful ITM. These insights emphasize the necessity of taking into account each drug’s unique pharmacokinetic and pharmacodynamic properties, along with the physiological characteristics of the target tissue, in determining the suitability of ITM

Selection for linear structure models with different variances

This paper is concerned with selection of some linear structure models with different variances. The models are based on the study of relationships between two fracture toughness testing methods of dental luting cemments. The measurements are made by using several kinds of materials. They are assumed to have different variances depending on the materials, but they have the same variance between two testing methods. For such data, we consider three types of structures between two methods: (1) proportionality, (2) linearity, and (3) no structure. We give Akaike information criterion, AIC, to evaluate these models. Then, we derive corrected AIC (CAIC) which is useful for small samples. By simulation experiments, we find that CAIC is more effective than AIC in the case of small samples. Our results are applied to a real data of dental luting cements.【査読有

Oral lichenoid drug reaction with autoantibodies in peripheral blood: Case report

AbstractA 51-year-old man complained of oral roughness and pain. At the age of 49 years, he was admitted for 8 months for bipolar emotional disorder. Oral administration of lithium carbonate was started. Extensive, hemorrhagic, erythema-mixed white lace-like patches were noted on the lip, buccal mucosae, and lingual margins. On biopsy, all lesions were consistent with oral lichen planus. A drug lymphocyte stimulation test showed a positive reaction to lithium carbonate. Blood examination revealed marked increases in the peripheral blood levels of antinuclear antibodies. To relieve the symptoms, the systemic administration of prednisolone was performed while continuing the lithium carbonate

Safety, health, and environmental assessment of bioethanol production from sugarcane, corn, and corn stover

Biofuels as renewable resources are one of the options to meet the challenges of fossil fuel resource depletion and atmospheric pollution. Several studies have focused on the technical, economic, and environmental footprint of biofuels, particularly bioethanol production. However, there has been little effort to incorporate the environmental, health, and safety (EHS) hazards in an inclusive sustainability assessment of bioethanol production alternatives. This study focuses on these sustainability aspects for bioethanol production by employing the EHS and the inherent safety index (ISI) methods. The multicriteria assessment also includes the cumulative energy demand as a widely used lifecycle impact assessment indicator. Sugarcane, corn, and corn stover are considered as biomass resources, and the typical process conditions are used for the base case evaluation. Sensitivity analysis is used to investigate the impact of process conditions, composition of feed, and method settings on the final outcome. The results indicate that both the ISI and the EHS methods present similar overall rankings with sugarcane-derived and corn stover-derived processes as the most and the least hazardous, respectively. However, dissimilarities occur in the evaluation of the process sections, highlighting different hazardous aspects. Finally, including the lifecycle impact assessment in a bicriteria assessment indicates the sugarcane-derived process as clearly superior followed by the corn-derived and the corn stover-derived processe

Safety, health, and environmental assessment of bioethanol production from sugarcane, corn, and corn stover

Biofuels as renewable resources are one of the options to meet the challenges of fossil fuel resource depletion and atmospheric pollution. Several studies have focused on the technical, economic, and environmental footprint of biofuels, particularly bioethanol production. However, there has been little effort to incorporate the environmental, health, and safety (EHS) hazards in an inclusive sustainability assessment of bioethanol production alternatives. This study focuses on these sustainability aspects for bioethanol production by employing the EHS and the inherent safety index (ISI) methods. The multicriteria assessment also includes the cumulative energy demand as a widely used lifecycle impact assessment indicator. Sugarcane, corn, and corn stover are considered as biomass resources, and the typical process conditions are used for the base case evaluation. Sensitivity analysis is used to investigate the impact of process conditions, composition of feed, and method settings on the final outcome. The results indicate that both the ISI and the EHS methods present similar overall rankings with sugarcane-derived and corn stover-derived processes as the most and the least hazardous, respectively. However, dissimilarities occur in the evaluation of the process sections, highlighting different hazardous aspects. Finally, including the lifecycle impact assessment in a bicriteria assessment indicates the sugarcane-derived process as clearly superior followed by the corn-derived and the corn stover-derived processe

Oxidative Dehydrogenation of Methane When Using TiO2- or WO3-Doped Sm2O3 in the Presence of Active Oxygen Excited with UV-LED

There are active oxygen species that contribute to oxidative coupling or the partial oxidation during the oxidative dehydrogenation of methane when using solid oxide catalysts, and those species have not been definitively identified. In the present study, we clarify which of the active oxygen species affect the oxidative dehydrogenation of methane by employing photo-catalysts such as TiO2 or WO3, which generate active oxygen from UV-LED irradiation conditions under an oxygen flow. These photo-catalysts were studied in combination with Sm2O3, which is a methane oxidation coupling catalyst. For this purpose, we constructed a reaction system that could directly irradiate UV-LED to a solid catalyst via a normal fixed-bed continuous-flow reactor operated at atmospheric pressure. Binary catalysts prepared from TiO2 or WO3 were either supported on or kneaded with Sm2O3 in the present study. UV-LED irradiation clearly improved the partial oxidation from methane to CO and/or slightly improved the oxidative coupling route from methane to ethylene when binary catalysts consisting of Sm2O3 and TiO2 are used, while negligible UV-LED effects were detected when using Sm2O3 and WO3. These results indicate that with UV-LED irradiation the active oxygen of O2− from TiO2 certainly contributes to the activation of methane during the oxidative dehydrogenation of methane when using Sm2O3, while the active oxygen of H2O2 from WO3 under the same conditions afforded only negligible effects on the activation of methane

Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin

A hallmark of clear cell renal cell carcinoma (ccRCC) is the presence of intracellular lipid droplets (LD) and it is assumed that phosphatidic acid (PA) produced by phospholipase D (PLD) plays some role in the LD formation. However, little is known about the significance of PLD in ccRCC. In this study, we examined the expression levels of PLD in ccRCC. The classical mammalian isoforms of PLD are PLD1 and PLD2, and the levels of both mRNA were higher at the primary tumor sites than in normal kidney tissues. Similarly, both PLD were significantly abundant in tumor cells as determined by analysis using immunohistochemical staining. Importantly, a higher level of PLD was significantly associated with a higher tumor stage and grade. Because PLD2 knockdown effectively suppressed the cell proliferation and invasion of ccRCC as compared with PLD1 in vitro, we examined the effect of PLD2 in vivo. Notably, shRNA‐mediated knockdown of PLD2 suppressed the growth and invasion of tumors in nude mouse xenograft models. Moreover, the higher expression of PLD2 was significantly associated with poorer prognosis in 67 patients. As for genes relating to the tumor invasion of PLD2, we found that angiogenin (ANG) was positively regulated by PLD2. In fact, the expression levels of ANG were elevated in tumor tissues as compared with normal kidney and the inhibition of ANG activity with a neutralizing antibody significantly suppressed tumor invasion. Overall, we revealed for the first time that PLD2‐produced PA promoted cell invasion through the expression of ANG in ccRCC cells

精神疾患におけるマイクログリア由来ニューレグリン発現

Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.博士（医学）・乙第1404号・平成29年6月28日Copyright © 2017 Elsevier Inc. All rights reserved

多数の静脈石を伴った巨大な舌血管腫の1例

A case of gigantic hemangioma of the tongue with numerous phlebohths is reported The patient was a 77-year-old woman with a chief complaint of eating disturbance due to the swollen mass of the tongue Intra-oral examination revealed a lobulated, well circumscribed gigantic tumor mass of the tongue measuring 62×61×49mm, purplish-red in color On palpation, the tumor was compressible, and had numerous phlebohths In the tumor, over fifty radiopaque phlebohths were detected and no influx vessels were observed by angiography The tumor was surgically excised and the postoperative course was uneventful