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Ozoralizumab is a bispecific NANOBODY compound that binds tumor necrosis factor alpha (TNFα) and human serum albumin. Ozoralizumab inhibits the TNFα physiological activity while maintaining long‐term plasma retention owing to its human serum albumin–binding ability. A population pharmacokinetic (PK) model was developed using data from 494 Japanese patients with rheumatoid arthritis in Phase II/III and Phase III trials to assess the effects of potential PK covariates. The ozoralizumab PK after subcutaneous administration was described using a 1‐compartment model with first‐order absorption and first‐order elimination processes. A proportional error model was used for inter‐ and intra‐individual variabilities, with covariance set between inter‐individual variabilities of the apparent clearance and apparent distribution volume. Body weight, sex, antidrug antibody status, estimated glomerular filtration rate, and concomitant methotrexate use were identified as covariates for apparent clearance, while body weight and sex were covariates for apparent distribution volume in the final model. Body weight had the greatest effect on the PK of ozoralizumab, while the other covariates had minor effects. When administered at 30 mg every 4 weeks, the predicted steady‐state plasma trough concentration in a patient weighing 83.2 kg exceeded the trough concentration required to maintain efficacy of ozoralizumab, and the estimated exposure in a patient weighing 42.5 kg did not exceed the mean exposure at 80 mg, a well‐tolerated dose, throughout 52 weeks. We developed a population PK model that adequately described the ozoralizumab PK in Japanese patients with rheumatoid arthritis, and none of the evaluated covariates showed clinically relevant effects on the PK of ozoralizumab. [ABSTRACT FROM AUTHOR]

The purpose of this study was to predict the drug-drug interactions ( DDIs) via CYP3A4 by estimating the extent of hepatic CYP3A4 inhibition based on a physiologically based pharmacokinetic ( PBPK) model of both substrate and inhibitor and the increase in the intestinal availability ( Fg) due to the enzyme inhibition. For the DDIs resulting from reversible inhibition of CYP3A4, the prediction using in vivo Ki values estimated from other clinical DDI studies and predicted in vivo Ki values calculated using the correlation between the log P and the in vivo Ki/ in vitro Ki ratio was more accurate than that using in vitro Ki values. Incorporating inhibition of both intestinal and hepatic metabolism resulted in better prediction than that obtained considering inhibition in the liver alone, and all the DDIs ( AUC increase by the inhibitor) were predicted within 2-fold accuracy when in vivo Ki values were used. In addition, Fg values were successfully back-calculated from the clinical DDI data based on the present model. In conclusion, the present PBPK model incorporating the in vivo Ki values was found to be useful for quantitative prediction of clinical DDIs and for estimation of the Fg values for CYP3A4 substrates for which intravenous data were not available. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3183-3193, 2015 [ABSTRACT FROM AUTHOR]

Abstract: The representation of social interaction in episodic memory is a critical factor for the successful navigation of social relationships. In general, it is important to separate episodic memory during social interaction from episodic memory during the self-generation of action events. Different cortical representations have been associated with social interaction vs. self-generated episodic memory. Here we clarified the cortical representation of the effect of context (social vs. solitary) on episodic memory by comparing it with the generation effect (self vs. other) on episodic memory. Each participant learned words while engaged in a sentence generation and a reading task, and subsequently each participant was scanned with functional magnetic resonance imaging (fMRI) while they performed a recognition task using the words that had been learned. The experiment was comprised of four conditions and we looked at two situations that involved a social context and non-social (solitary) context task. In the learning session before entering the MRI, two participants collaborated in a social context either generating (social–contextual self-generation condition: SS) or reading (social–contextual other-generation condition: SO) a sequence of sentences alternately to construct a meaningful story narrative. In the non-social context, the participants generated (non-social–contextual self-generation condition: NS) or read (non-social–contextual other-generation condition: NO) a sequence of sentences individually. The stimuli for the recognition session consisted of learned words and novel words. Activation for social context retrieval was identified in the right medial prefrontal cortex (mPFC), and activation for self-generated retrieval was identified in the left mPFC and the left middle cingulate cortex. These results indicate that dissociable regions within the medial prefrontal cortices contribute to the processes involved in the representation of social interaction, including social context and self-generation in the retrieval of episodic memory. [Copyright &y& Elsevier]

Memory for person identity information consists of three main components: face-related information, name-related information, and person-related semantic information, such as the person's job title. Although previous studies have demonstrated the importance of the anterior temporal lobe (ATL) in the retrieval of associations between these kinds of information, there is no evidence concerning whether the ATL region contributes to the encoding of this memory, and whether ATL roles are dissociable between different levels of association in this memory. Using fMRI, we investigated dissociable roles within the ATL during successful encoding of this memory. During encoding, participants viewed unfamiliar faces, each paired with a job title and name. During retrieval, each learned face was presented with two job titles or two names, and participants were required to choose the correct job title or name. Successful encoding conditions were categorized by subsequent retrieval conditions: successful encoding of names and job titles (HNJ), names (HN), and job titles (HJ). The study yielded three main findings. First, the dorsal ATL showed greater activations in HNJ than in HN or HJ. Second, ventral ATL activity was greater in HNJ and HJ than in HN. Third, functional connectivity between these regions was significant during successful encoding. The results are the first to demonstrate that the dorsal and ventral ATL roles are dissociable between two steps of association, associations of person-related semantics with name and with face, and a dorsal-ventral ATL interaction predicts subsequent retrieval success of memory for person identity information. [ABSTRACT FROM AUTHOR]

Abstract: During narrative comprehension, readers understand the emotions of the protagonist by taking the perspective of the character, which is an essential component of empathy. Spatial perspective-taking is crucial to understanding the standpoints and perceptions of others, and gives clues as to what the protagonist knows. As a default, a “here and now” point-of-view is adopted to make sense of the narrative. If the protagonist is in a different location while an event takes place (“there and now”), in order to comprehend the narrative the reader must take an allocentric perspective, which places greater demands on spatial perspective-taking. Utilizing this phenomenon, we evaluated the neural substrates of perspective-taking in emotional narrative comprehension using functional MRI in 18 normal adults. The subjects read short stories followed by a target sentence, which described an event that might evoke an emotional response in the protagonist if the character were present. The stories involved a scenario in which the character was either present at the same location (“here and now”) or at a distant location (“there and now”) during the event. The “there and now” scenario activated the posterior cingulate cortex and the right temporo-parietal junction more prominently than the “here and now” condition. In contrast to the control tasks, both scenarios activated the well-known mentalizing network including the dorsomedial prefrontal cortex, temporal pole, posterior cingulate cortex and temporo-parietal junction. Along with the mentalizing network, the posterior cingulate cortex and the right temporo-parietal junction are involved in spatial perspective-taking during emotional narrative comprehension. [Copyright &y& Elsevier]

Cultural factors, such as cultural group membership, have been shown to affect neural bases of face and emotion perception. However, little is known about how cultural factors influence neural processing of emotional faces expressed by in-group and out-group members. In this study, we examined cultural influences on neural activation during the intergroup perception of negative emotional faces. We used functional magnetic resonance imaging to compare neural activation during intergroup emotion processing across cultures in three participants groups; two monocultural groups (i.e. Caucasian-Americans and native Japanese) and a bicultural group (i.e. Japanese-Americans). During scanning, the participants completed an emotional match-to-sample task consisting of negative facial expressions of Japanese and Caucasians. Our results show cultural modulation of neural response in the bilateral amygdala as a function of in-group biases and collectivistic values. Additionally, bicultural Japanese-Americans showed enhanced neural responses in the ventral medial prefrontal and posterior cingulate cortices, which had been related to self-related processing, during the perception of negative facial expression of Japanese. Neural activation in the ventral and posterior cingulate cortices reflected individuals' collectivistic tendencies only in the Japanese-American group, possibly due to greater sensitivity to ingroup biases in bicultural individuals. Our results demonstrate the influence of culture on neural responses during the perception of intergroup emotion from faces. • Cultural and racial factors affect how people perceive intergroup negative emotion. • Culture shapes bilateral amygdala response to ingroup negative facial expressions. • Biculturals showed greater neural response to in-group negative emotional faces. • Self-related processing was enhanced for racially in-group faces in biculturals. • These findings demonstrate the influence of cultural and racial factors on neural response to intergroup emotion. [ABSTRACT FROM AUTHOR]

We evaluated the in vitro drug–drug interaction (DDI) potential of enerisant (TS-091), a histamine H3 receptor antagonist/inverse agonist, mediated by cytochrome P450 (CYP) and transporters, as well as the pharmacokinetics of enerisant in healthy male subjects. Enerisant did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4. Enerisant inhibited organic cation transporter 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2-K, but not P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, or OAT3. Enerisant was a substrate for P-gp, but not for eight other transporters. In healthy male subjects, enerisant was rapidly absorbed after oral administration, and the plasma concentration increased dose-dependently. The urinary excretion of enerisant within 48 h after administration was 64.5% to 89.9% of the dose, indicating that most of the absorbed enerisant was excreted in the urine without being metabolized. Based on the plasma concentrations at the estimated clinical dose, enerisant is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Implicit or automatic detection of social signals, which discriminate animate, intentional objects in the environment, is essential for higher social cognition and its development. Using functional magnetic resonance imaging, we identified the neural substrate of detecting simple visual social signals and examined its functional link with the mechanism of inferring another’s mental state. Healthy participants were presented with the eye-gaze shift (EG) and self-propelling motion (SP) under both implicit and explicit task conditions. They also performed a social role-playing game in which mental inference (MI) was implicitly prompted during the presentation of faces (implicit MI). Implicit detection of EG and SP activated the posterior middle temporal gyrus (pMTG) bilaterally, whereas the right posterior superior temporal sulcus was activated during the explicit conditions. We revealed that the individual variation in neural response in the right pMTG during implicit eye-gaze detection explains the individual tendency to recruit the regions implicated in mental-state inference (medial prefrontal cortex, temporal pole and striatum) during the implicit MI task. Our results suggest that the implicit detection of visual social signals involves the pMTG and underlies the development of higher social cognition. [ABSTRACT FROM PUBLISHER]

Background: Research has shown that some microbiomes are linked to cancer. Hence, we hypothesize that alterations in the respiratory microbiome might be associated with lung cancer. Methods: Through droplet digital polymerase chain reaction analysis, we investigated the abundance of Acidovorax in surgically resected primary tumors and corresponding nontumor lung tissues obtained from 50 Japanese patients with non‐small cell lung cancer. Results: The rate of positivity for Acidovorax in tumor and nontumor tissues was 44 and 26%, respectively. The abundance of Acidovorax in tumor tissues was significantly higher in patients with nonsquamous cell carcinoma complicated by chronic obstructive pulmonary disease (COPD) and those who relapsed after surgical resection (p < 0.05). In tumor tissues, the results of the univariate and multivariate analyses revealed that only COPD exerted a direct effect on the abundance of Acidovorax (p < 0.05). Furthermore, the presence of Acidovorax was high in lung cancer patients with COPD comorbidity (65%) and TP53 gene mutation; only one of the nontumor tissues was positive for Acidovorax. In patients with lung cancer complicated by COPD, Acidovorax tended to be present in both the tumor and nontumor areas. Conclusions: This study identified novel microbiota involved in lung cancer with COPD comorbidity. The results suggested that Acidovorax may be a useful biomarker in the screening for lung cancer. Further studies are warranted to validate the clinical significance of the microbiome in a larger independent patient cohort. [ABSTRACT FROM AUTHOR]

1. We evaluated potentialin vitrodrug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively. 2. Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC50value of 58.3 μM, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72 hrs weakly induced CYP3A4 at a concentration of 10 μM, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1–10 μM. 3. Anin vitrotransport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC50value of 93.1 μM, but those for other transporters are greater than 100 μM. 4. Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters. [ABSTRACT FROM PUBLISHER]

Research on neural basis of inhibitory control has been extensively conducted in various parts of the world. It is often implicitly assumed that neural basis of inhibitory control is universally similar across cultures. Here, we investigated the extent to which culture modulated inhibitory-control brain activity at both cultural-group and cultural-value levels of analysis. During fMRI scanning, participants from different cultural groups (including Caucasian-Americans and Japanese-Americans living in the United States and native Japanese living in Japan) performed a Go/No-Go task. They also completed behavioral surveys assessing cultural values of behavioral consistency, or the extent to which one's behaviors in daily life are consistent across situations. Across participants, the Go/No-Go task elicited stronger neural activity in several inhibitory-control areas, such as the inferior frontal gyrus (IFG) and anterior cingulate cortex (ACC). Importantly, at the cultural-group level, we found variation in left IFG (L-IFG) activity that was explained by a cultural region where participants lived in (as opposed to race). Specifically, L-IFG activity was stronger for native Japanese compared to Caucasian- and Japanese-Americans, while there was no systematic difference in L-IFG activity between Japanese- and Caucasian-Americans. At the cultural-value level, we found that participants who valued being “themselves” across situations (i.e., having high endorsement of behavioral consistency) elicited stronger rostral ACC activity during the Go/No-Go task. Altogether, our findings provide novel insight into how culture modulates the neural basis of inhibitory control. [ABSTRACT FROM AUTHOR]

Individuals with autism spectrum disorder (ASD) are thought to lack self-awareness and to experience difficulty empathizing with others. Although these deficits have been demonstrated in previous studies, most of the target stimuli were constructed for typically developing (TD) individuals. We employed judgment tasks capable of indexing self-relevant processing in individuals with and without ASD. Fourteen Japanese men and 1 Japanese women with high-functioning ASD (17–41 years of age) and 13 Japanese men and 2 TD Japanese women (22–40 years of age), all of whom were matched for age and full and verbal intelligence quotient scores with the ASD participants, were enrolled in this study. The results demonstrated that the ventromedial prefrontal cortex was significantly activated in individuals with ASD in response to autistic characters and in TD individuals in response to non-autistic characters. Although the frontal–posterior network between the ventromedial prefrontal cortex and superior temporal gyrus participated in the processing of non-autistic characters in TD individuals, an alternative network was involved when individuals with ASD processed autistic characters. This suggests an atypical form of empathy in individuals with ASD toward others with ASD. [ABSTRACT FROM AUTHOR]

Elucidating the neural mechanisms involved in aversive conditioning helps find effective treatments for psychiatric disorders such as anxiety disorder and phobia. Previous studies using fMRI and human subjects have reported that the amygdala plays a role in this phenomenon. However, the noxious stimuli that were used as unconditioned stimuli in previous studies (e.g., electric shock) might have been ecologically invalid because we seldom encounter such stimuli in daily life. Therefore, we investigated whether a face stimulus could be conditioned by using a voice that had negative emotional valence and was collected from a real-life environment. A skin conductance response showed that healthy subjects were conditioned by using these stimuli. In an fMRI study, there was greater amygdala activation in response to the faces that had been paired with the voice than to those that had not. The right amygdala showed transient activity in the early stage of acquisition. A psychophysiological interaction analysis indicated that the subcortical pathway from the medial geniculate body to the amygdala played a role in conditioning. Modulation of the subcortical pathway by voice stimuli preceded the transient activity in the amygdala. The finding that an ecologically valid stimulus elicited the conditioning and amygdala response suggests that our brain is automatically processing unpleasant stimuli in daily life. [ABSTRACT FROM AUTHOR]

Cultural neuroscience is an emerging research discipline that investigates cultural variation in psychological, neural and genomic processes as a means of articulating the bidirectional relationship of these processes and their emergent properties. Research in cultural neuroscience integrates theory and methods from anthropology, cultural psychology, neuroscience and neurogenetics. Here, we review a set of core theoretical and methodological challenges facing researchers when planning and conducting cultural neuroscience studies, and provide suggestions for overcoming these challenges. In particular, we focus on the problems of defining culture and culturally appropriate experimental tasks, comparing neuroimaging data acquired from different populations and scanner sites and identifying functional genetic polymorphisms relevant to culture. Implications of cultural neuroscience research for addressing current issues in population health disparities are discussed. [ABSTRACT FROM PUBLISHER]

People living in multicultural environments often encounter situations which require them to acquire different cultural schemas and to switch between these cultural schemas depending on their immediate sociocultural context. Prior behavioral studies show that priming cultural schemas reliably impacts mental processes and behavior underlying self-concept. However, less well understood is whether or not cultural priming affects neurobiological mechanisms underlying the self. Here we examined whether priming cultural values of individualism and collectivism in bicultural individuals affects neural activity in cortical midline structures underlying self-relevant processes using functional magnetic resonance imaging. Biculturals primed with individualistic values showed increased activation within medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) during general relative to contextual self-judgments, whereas biculturals primed with collectivistic values showed increased response within MPFC and PCC during contextual relative to general self-judgments. Moreover, degree of cultural priming was positively correlated with degree of MPFC and PCC activity during culturally congruent self-judgments. These findings illustrate the dynamic influence of culture on neural representations underlying the self and, more broadly, suggest a neurobiological basis by which people acculturate to novel environments. [ABSTRACT FROM AUTHOR]

Individualism and collectivism refer to cultural values that influence how people construe themselves and their relation to the world. Individualists perceive themselves as stable entities, autonomous from other people and their environment, while collectivists view themselves as dynamic entities, continually defined by their social context and relationships. Despite rich understanding of how individualism and collectivism influence social cognition at a behavioral level, little is known about how these cultural values modulate neural representations underlying social cognition. Using cross-cultural functional magnetic resonance imaging (fMRI), we examined whether the cultural values of individualism and collectivism modulate neural activity within medial prefrontal cortex (MPFC) during processing of general and contextual self judgments. Here, we show that neural activity within the anterior rostral portion of the MPFC during processing of general and contextual self judgments positively predicts how individualistic or collectivistic a person is across cultures. These results reveal two kinds of neural representations of self (eg, a general self and a contextual self) within MPFC and demonstrate how cultural values of individualism and collectivism shape these neural representations. Hum Brain Mapp, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]