[This corrects the article DOI: 10.3389/fphar.2022.1037983.].

Background: An antibody specific to small-molecule inhibitor-bound TNF has enabled the development of target occupancy biomarker assays to support the development of novel treatments for autoimmune disorders. Materials & methods: ELISAs were developed for inhibitor-bound and total TNF to determine the percentage of TNF occupancy in samples from stimulated blood. Inhibitor-saturated samples allowed measurement of total and inhibitor-bound TNF in a single electrochemiluminescence immunoassay. Results: TNF occupancy was proportional to inhibitor concentration in plasma samples. An electrochemiluminescence method for inhibitor-bound TNF was validated for use as a potential clinical occupancy biomarker assay. Conclusion: Development of these assays has allowed measurement of a target occupancy biomarker, which has supported progression of the first small-molecule inhibitors of TNF.

Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.

This chapter focuses on factors influencing regional epithelial permeation of drugs related especially to transporters. It highlights the important key messages as regard to modified-release formulations. Drug absorption for ionizable drugs is determined by the pH in the region of intended release. Uptake and efflux transporters expressed in the gastrointestinal tract modulate the absorption of several drugs. Uptake transporters are more likely to act in synergy with other enzymes whose regional distribution is similar to CYP3A4, such as glucuronosyltransferases, sulfotransferases, and glutathione-S-transferases. The impact of the interplay between drug transport and metabolism on regional absorption can also be studied with perfusion techniques using cannulated in situ or isolated ex vivo intestinal regions in the rat. Drug–drug interactions can lead to changed systemic exposure, resulting in variations in drug response of the coadministered drug/s as well as safety concerns especially for low therapeutic index drugs.

The current study examined prescribing patterns of anticholinergic (AC) medications and their association with cognitive function in 450 nondemented and nondelirious older adults hospitalized in a postacute extended care center. Participants completed a brief neuropsychological battery that included measures of general mental status, memory, judgment, and executive functioning as part of standard clinical care. An AC burden score was calculated for each participant based on medications taken the day of the testing using the Anticholinergic Drug Scale. Although use of AC medications was common, the majority of participants were taking medications with only minimal AC properties. AC burden and total number of AC medications were negatively correlated with age. AC burden was not associated with lower performance on any of the cognitive measures. In sum, current prescribing practices of AC medications are not associated with negative cognitive effects in a sample of older adults hospitalized in an extended care center.

Depression predicts fall risk among older adults, and this relationship may be partially explained by depression-associated executive dysfunction, relevant to navigating demanding environments. This pilot study examined timed stepping accuracy under simple and complex dual-task conditions, using an instrumented walkway based on the Trail Making Test. Participants were balance-impaired older adults, either with (n = 8; major depressive disorder [MDD]) or without (n = 8; nondepressed [ND]) MDD. After accounting for comfortable gait speed and age, the MDD group was significantly slower than the ND group on the walkway with the highest cognitive demand and demonstrated greater dual-task cost, both of which were correlated with performance on traditional measures of executive functioning. No group differences were observed on the walkway with the least cognitive demand. Balance-impaired older adults with MDD demonstrate increased stepping accuracy time under cognitively demanding conditions, reflecting executive dysfunction and an additional contribution to increased fall risk.

This study examined stereotypes of older lesbians and gay men. Key findings are that older lesbians and gay men were perceived as similar to older heterosexual women and men with regard to aging stereotypes, such as being judicious. At the same time, sexual minorities were targets of unique stereotypes. Consistent with the implicit inversion theory, lesbians were conceived as similar to heterosexual men, and gay men similar to heterosexual women with regard to gender-stereotypic traits, and regardless of age. These findings suggest the persistence into late adulthood of the belief that lesbians and gay men are inverted females and males.

Background: One of the principal theories regarding the biological basis of major depressive disorder (MDD) implicates a dysregulation of emotion‐processing circuitry. Gender differences in how emotions are processed and relative experience with emotion processing might help to explain some of the disparities in the prevalence of MDD between women and men. This study sought to explore how gender and depression status relate to emotion processing. Methods: This study employed a 2 (MDD status) × 2 (gender) factorial design to explore differences in classifications of posed facial emotional expressions (N=151). Results: For errors, there was an interaction between gender and depression status. Women with MDD made more errors than did nondepressed women and men with MDD, particularly for fearful and sad stimuli (Ps <.02), which they were likely to misinterpret as angry (Ps <.04). There was also an interaction of diagnosis and gender for response cost for negative stimuli, with significantly greater interference from negative faces present in women with MDD compared to nondepressed women (P=.01). Men with MDD, conversely, performed similarly to control men (P=.61). Conclusions: These results provide novel and intriguing evidence that depression in younger adults (<35 years) differentially disrupts emotion processing in women as compared to men. This interaction could be driven by neurobiological and social learning mechanisms, or interactions between them, and may underlie differences in the prevalence of depression in women and men. Depression and Anxiety, 2009. Published 2008 Wiley‐Liss, Inc.

Background: Differences in emotion processing during Major Depressive Disorder (MDD) have not been well explored as a potential explanation for age and gender disparities in rates of depression and depressive symptoms. Early studies by our group demonstrated that those with MDD underperform in emotion processing of faces, although recently we showed a selective decrement in young women with MDD. We now extend this study of gender differences in facial emotion processing during MDD to the full age spectrum. We assessed emotion processing performance using posed facial emotional expressions in those with early (age < 36) and late (age > 35) MDD as well as in women and men to determine if there was differential impact of MDD in these four groups. We hypothesized that knowledge about gender, age, and emotion processing performance differences might increase understanding of risk for and expression of MDD in women and in those with later onset MDD. Methods: Participants included 161 young adults (123 women, 38 men) and 150 adults (100 women, 50 men) diagnosed with MDD, as well as 97 young adult (60 women, 37 men) and 35 adult (24 women, 11 men) healthy controls. A conservative age classification ≤ age 35 was used to separate young adult and adult control and MDD groups in order to be to be confident that potential causes of late onset MDD (e.g., cardiovascular) were less likely to be present in the young adult MDD groups. Results: There was an interaction between age, gender, and MDD status for response time, with slower response times in young MDD patients compared to their age-matched control groups. This effect of slower response time was not detected in the comparisons Sara L. Wright and Scott A. Langenecker 2 between adults with and without MDD. Young adult and adult women and adult men with MDD made significantly more errors than did their same-age, same-gender control counterparts (ps < .05), whereas young men with MDD performed similarly to same-age control men (p > .26). Further, although adult women and men with MDD performed more poorly in facial perception relative to same age control cohorts, older men with late onset MDD performed worse than older men with early onset MDD, in contrast to no difference between performance of women with late and early onset MDD. Conclusions: These findings suggest that young men with MDD may have a different neurobiological etiology of depression compared to young women. In contrast, older men and all women with MDD appear to have similar difficulties with emotion processing, suggesting comparable neurobiological mechanisms of illness. Notably, older men with late onset MDD appear to have a greater burden of emotion processing deficit compared to other depressed groups.

4-(1,3-Thiazol-2-yl)morpholine derivatives have been identified as potent and selective inhibitors of phosphoinositide 3-kinase. The SAR data of selected examples are presented and the in vivo profiling of compound 18 is shown to demonstrate the utility of this class of compounds in xenograft models of tumor growth.

The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.