Southwest Research Institute assistance to NASA in biomedical areas of the technology utilization program Quarterly progress report, 1 Jul. - 30 Sep. 1968

Southwest Research Institute activites in NASA technology utilization program for biomedical use, 1 Jul. - 30 Sep. 196

Southwest Research Institute assistance to NASA in biomedical areas of the technology utilization program Cumulative quarterly report, 1 Apr. - 30 Jun. 1968

Biomedical applications of NASA science and technolog

Social functioning as a mediator between Developmental Language Disorder (DLD) and emotional problems in adolescents

Adolescents with Developmental Language Disorder (DLD) are at risk for increased feelings of anxiety and depression compared to their typically developing (TD) peers. However, the underlying pathways involved in this relationship are unclear. In this initial study of the ‘social mediation hypothesis’ we examine social functioning as a mediator of emotional problems in a cross-sectional sample of adolescents with DLD and age- and sex-matched controls. Preliminary data from twenty-six participants with DLD and 27 participants with typical language development (TLD, 11-17 years) were compared on self- and parent-reported measures of social functioning and emotional outcomes. There was little evidence of group differences in self-reported social functioning and emotional outcomes, but parent-report of SDQ Peer Problems and Emotional Problems in the DLD group was significantly higher than in the TLD group. Parent-reported peer problems mediated parent-reported emotional problems, accounting for 69% of the relationship between DLD status and emotional problems. Parents of adolescents with DLD, but not adolescents themselves, report significantly higher peer and emotional problems compared to TLD peers. The hypotheses generated from these novel data suggest further investigation into adolescents’ perceptions of socioemotional difficulties and friendships should be examined

Southwest Research Institute assistance to NASA in biomedical areas of the technology utilization program Final report, 1 Nov. 1967 - 30 Nov. 1968

Southwest Research Institute activities in technology utilization program in biomedical areas, Nov. 1967 - Nov. 196

Social Cognition in Adolescents with Developmental Language Disorder (DLD): Evidence from the Social Attribution Task

Social cognition impairments may explain social, emotional and behavioural difficulties (SEBD) in individuals with Developmental Language Disorder (DLD). In a novel approach, the Social Attribution Task (SAT) was used to examine this association. SAT narratives were coded from 53 participants [n = 26 DLD; n = 27 typical language development (TLD)] matched on age (Mage = 13;6) and gender (35.9% female). Parents reported SEBD. Adolescents with DLD performed worse than their TLD peers on the majority of SAT indices and had higher peer (d = 1.09) and emotional problems (d = .75). There was no association between social cognition abilities and SEBD. These exploratory findings suggest social cognition should be further examined in this population

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be employed to construct physiologically-based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been employed to study cytotoxicity and perturbation of biological processes by drugs and hepatically-generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model was used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes

Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP 3A. The present study investigated the hepatocellular disposition of tolvaptan and the generated tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatography–tandem mass spectrometry. Pioglitazone, verapamil, MK-571, and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by tolvaptan and metabolites. Cellular accumulation of tolvaptan (0.15–50 μM), DM-4103, and DM-4107 in SCHH was concentration-dependent. Tolvaptan accumulation (15 μM) in SCHH was not altered markedly by 50 μM pioglitazone, verapamil, MK-571, or 10 μM elacridar. Coincubation of tolvaptan with pioglitazone, verapamil, MK-571, and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5, and 23.0%, respectively, relative to control. Coincubation with increasing tolvaptan concentrations (0.15–50 μM) decreased TCA (2.5 μM) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μM) had no effect on the cellular accumulation of 2.5 μM pravastatin or metformin. Digoxin cellular accumulation increased, and the BEI of digoxin decreased from 23.9 to 8.1% in the presence of 15 μM tolvaptan, consistent with inhibition of P-glycoprotein. In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving tolvaptan and metabolites

Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes

Sandwich-cultured hepatocytes (SCH) are used commonly to investigate hepatic transport protein-mediated uptake and biliary excretion of substrates. However, little is known about the disposition of endogenous bile acids (BAs) in SCH. In this study, four endogenous conjugated BAs common to rats and humans [taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and glycochenodeoxycholic acid (GCDCA)], as well as two BA species specific to rodents (α- and β-tauromuricholic acid; α/β TMCA), were profiled in primary rat and human SCH. Using B-CLEAR® technology, BAs were measured in cells+bile canaliculi, cells, and medium of SCH by LC-MS/MS. Results indicated that, just as in vivo, taurine-conjugated BA species were predominant in rat SCH, while glycine-conjugated BAs were predominant in human SCH. Total intracellular BAs remained relatively constant over days in culture in rat SCH. Total BAs in control (CTL) cells+bile, cells, and medium were approximately 3.4, 2.9, and 8.3-fold greater in human than in rat. The estimated intracellular concentrations of the measured total BAs were 64.3 ± 5.85 μM in CTL rat and 183 ± 55.6 μM in CTL human SCH, while medium concentrations of the total BAs measured were 1.16 ± 0.210 μM in CTL rat SCH and 9.61 ± 6.36 μM in CTL human SCH. Treatment of cells for 24 h with 10 μM troglitazone (TRO), an inhibitor of the bile salt export pump (BSEP) and the Na+-taurocholate cotransporting polypeptide (NTCP), had no significant effect on endogenous BAs measured at the end of the 24-h culture period, potentially due to compensatory mechanisms that maintain BA homeostasis. These data demonstrate that BAs in SCH are similar to in vivo, and that SCH may be a useful in vitro model to study alterations in BA disposition if species differences are taken into account

Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

Tolvaptan is a vasopressin