Intravitreal Administration of Acetyl Triethyl Citrate and Benzyl Benzoate Is Retinotoxic in Rabbits but Not in Cynomolgus Monkeys.

Sustained drug delivery formulations are developed to reduce dose frequency while maintaining efficacy of intravitreal (ITV) administered therapeutics. Available safety data for components novel to the eye's posterior segment may be limited, requiring preclinical assessments to identify potential toxicities. We evaluated the in vivo and in vitro safety of two solvents, acetyl triethyl citrate (ATEC) and benzyl benzoate (BB), as novel sustained delivery formulations for ITV administration. In vivo tolerability was assessed following ITV administration of ATEC and BB to rabbits and cynomolgus monkeys. In rabbits, ITV solvent administration resulted in moderate to severe retinal toxicity characterized by focal retinal necrosis and/or degeneration, sometimes accompanied by inflammation, with a clear association between the physical presence of the solvent and areas of retinal damage. In contrast, solvent administration in monkeys appeared well tolerated, producing no histologic abnormalities. Toxicity in primary human retinal pigment epithelial cells, characterized by cellular toxicity and mitochondrial injury, corroborated the retinal toxicity in rabbits. In conclusion, ITV solvent depots of ATEC or BB result in chemical and focal retinal toxicity in rabbits, but not monkeys. Additional investigation is needed to demonstrate a sufficient margin of safety prior to use of ATEC or BB in ITV drug products.

In vitro assessment of farnesoid X receptor antagonism to predict drug-induced liver injury risk.

Drug-induced liver injury (DILI) continues to be a major cause of drug attrition and restrictive labeling. Given the importance of farnesoid X receptor (FXR) in bile acid homeostasis, drug-related FXR antagonism may be an important mechanism of DILI. However, a comprehensive assessment of this phenomenon broadly in the context of DILI is lacking. As such, we used an orthogonal approach comprising a FXR target gene assay in primary human hepatocytes and a commercially available FXR reporter assay to investigate the potential FXR antagonistic effects of an extensive test set of 159 compounds with and without association with clinical DILI. Data were omitted from analysis based on the presence of cytotoxicity to minimize false positive assay signals and other complications in data interpretation. Based on the experimental approaches employed and corresponding data, the prevalence of FXR antagonism was relatively low across this broad DILI test set, with 16-24% prevalence based on individual assay results or combined signals in both assays. Moreover, FXR antagonism was not highly predictive for identifying clinically relevant hepatotoxicants retrospectively, where FXR antagonist classification alone had minimal to moderate predictive value as represented by positive and negative likelihood ratios of 2.24-3.84 and 0.72-0.85, respectively. The predictivity did not increase significantly when considering only compounds with high clinical exposure (maximal or efficacious plasma exposures > 1.0 µM). In contrast, modest gains in predictive value of FXR antagonism were observed considering compounds that also inhibit bile salt export pump. In addition, we have identified novel FXR antagonistic effects of well-studied hepatotoxic drugs, including bosentan, tolcapone and ritonavir. In conclusion, this work represents a comprehensive evaluation of FXR antagonism in the context of DILI, including its overall predictivity and challenges associated with detecting this phenomenon in vitro.

Knowing when to trust a teacher: The contribution of category status and sample composition to young children's judgments of informant trustworthiness.

Two experiments examined the extent to which category status influences children's attention to the composition of evidence samples provided by different informants. Children were told about two informants, each of whom presented different samples of evidence, and then were asked to judge which informant they would trust to help them learn something new. The composition of evidence samples was manipulated such that one sample included either a large number (n = 5) or a diverse range of exemplars relative to the other sample, which included either a small number (n = 2) or a homogeneous range of exemplars. Experiment 1 revealed that participants (N = 37; Mage = 4.76 years) preferred to place their trust in the informant who presented the large or diverse sample when each informant was labeled "teacher" but exhibited no preference when each informant was labeled "child." Experiment 2 revealed developmental differences in responses when labels and sample composition were pitted against each other. Younger children (n = 32; Mage = 3.42 years) consistently trusted the "teacher" regardless of the composition of the sample the informant was said to have provided, whereas older children (n = 30; Mage = 5.54 years) consistently trusted the informant who provided the large or diverse sample regardless of whether it was provided by a "teacher" or a "child." These results have important implications for understanding the interplay between children's category knowledge and their evaluation of evidence.

Three-year-olds obey the sample size principle of induction: the influence of evidence presentation and sample size disparity on young children's generalizations.

Three experiments with 81 3-year-olds (M=3.62years) examined the conditions that enable young children to use the sample size principle (SSP) of induction-the inductive rule that facilitates generalizations from large rather than small samples of evidence. In Experiment 1, children exhibited the SSP when exemplars were presented sequentially but not when exemplars were presented simultaneously. Results from Experiment 3 suggest that the advantage of sequential presentation is not due to the additional time to process the available input from the two samples but instead may be linked to better memory for specific individuals in the large sample. In addition, findings from Experiments 1 and 2 suggest that adherence to the SSP is mediated by the disparity between presented samples. Overall, these results reveal that the SSP appears early in development and is guided by basic cognitive processes triggered during the acquisition of input.

Expectations about single event probabilities in the first year of life: The influence of perceptual and statistical information.

Recent evidence suggests that infants can generate expectations about future events from a sample of probabilistic data. However, little is known about the conditions that support the development of this ability. Three experiments tested the prediction that 8- and 12-month-olds respond to base rates as well as perceptual cues when they generate expectations from a sample of probabilistic data. Results revealed that 12-month-olds were sensitive to the statistical and perceptual properties of the evidence depending on the distribution of high-to-low base rate items in the sample. Specifically, 12-month-olds focused on perceptual features of the evidence when a sample was large and more skewed (e.g., 6:1), whereas they attended to statistical properties when the sample was smaller and less skewed (e.g., 4:1). In contrast, eight-month-olds always focused on the perceptual features of the evidence. Neither group generated expectations from a small, less skewed sample (e.g., 2:1). These results suggest that the ability to generate expectations about future events is mediated by specific features of the available evidence and undergoes significant change during the 1st year of life.

It's in the sample: the effects of sample size and sample diversity on the breadth of inductive generalization.

Developmental studies have provided mixed evidence with regard to the question of whether children consider sample size and sample diversity in their inductive generalizations. Results from four experiments with 105 undergraduates, 105 school-age children (M=7.2 years), and 105 preschoolers (M=4.9 years) showed that preschoolers made a higher rate of projections from large samples than from small samples when samples were diverse (Experiments 1 and 3) but not when samples were homogeneous (Experiment 4) and not when the task required a choice between two samples (Experiment 2). Furthermore, when a property occurred in large and diverse samples, preschoolers exhibited a broad pattern of projection, generalizing the property to items from categories not represented in the evidence. In contrast, adults followed a normative pattern of induction and never attributed properties to items from categories not represented in the evidence. School-age children showed a mixed pattern of results.

Sample selection and inductive generalization.

In two experiments with adults (N = 126), we examined the influence of sampling procedure on inductive generalization. In predicate sampling, participants learned the category identity of individuals known to possess some property. In subject sampling, individuals selected for category identity were discovered to possess a novel property. In both experiments, sampling procedure influenced induction. Predicate sampling resulted in very narrow generalization, whereas subject sampling yielded a fairly high and constant rate of projection. Differences in confidence of generalizations were also observed. Conditions in which evidence was described as randomly sampled from a collection of animals yielded a consistent decrease in projections as predicted by similarity-based models. The results are presented as support for an evidence-based view of induction.

A series of 2(Z)-2-benzylidene-6,7-dihydroxybenzofuran-3[2H]-ones as inhibitors of chorismate synthase.

A series of 2(Z)-2-benzylidene-6,7-dihydroxybenzofuran-3[2H]-ones was identified as potent inhibitors of bacterial chorismate synthase. The 2'-hydroxy-4'-pentoxy analogue 33 is a potent inhibitor of Streptococcus pneumoniae chorismate synthase.