Core Battery Research Articles

Reevaluating safety pharmacology respiratory studies within the ICH S7A core battery: A multi-company evaluation of preclinical utility and clinical translation

Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings. A large database of novel molecules included all relevant data from standard S7A respiratory (n = 459) and FIH studies (n = 309). The data were analyzed with respect to the progression of these molecules, clinical adverse event reporting of these same molecules, and achieved exposures. These S7A respiratory assay findings had no impact on compound progression, and only 12 of 309 drug candidates were ‘positive’ preclinically and reported a respiratory-related AE in clinical trials (i.e. cough, dyspnea, etc.), an overall incidence rate of 3.9%. Contingency tables/statistics support a lack of concordance of these preclinical assays. Overall, our extensive analysis clearly indicated that the preclinical respiratory assay fails to provide any prognostic value for detecting clinically relevant respiratory adverse events.

An improved solar step-up power converter for next-generation electric vehicle charging

This study proposes an innovative control strategy based on a quadratic equation derived from a core battery charging model. This strategy is applied to a solar step-up power converter (SSUPC), which is specifically optimized for electric vehicle charging. The model includes a 500 W SSUPC, controlled by a microprocessor, effectively converting low input voltage into high output voltage. The proposed control strategy allows the SSUPC to operate in discontinuous conduction mode, thereby achieving a higher voltage gain. In experiments with an input voltage of 20 V, the system was capable of outputting up to 480 V, while maintaining a low duty cycle of 0.3 and achieving a system conversion efficiency of 95 %. Furthermore, the SSUPC integrates a pyramid maximum power point tracking (MPPT) algorithm, initiating MPPT to capture the maximum power point when the solar output power is insufficient for electric vehicle charging, achieving an MPPT efficiency of 99 %. The developed charger is compact, boasts high power density, is cost-effective, and is well-suited for widespread application, meeting the 480 V charging requirements of electric vehicles.

Innovative approaches to cardiovascular safety pharmacology assessment

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods which has been published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). Here we highlight content derived from the 2023 Safety Pharmacology Society (SPS) meeting held in Brussels, Belgium. The meeting generated 138 abstracts, reproduced in the current volume of JPTM. As in prior years, the manuscripts reflect various areas of innovation in SP including in silico modeling of stroke volume, cardiac output and systemic vascular resistance, computational approaches that compare drug-induced proarrhythmic sensitivity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), an evaluation of the utility of the corrected J-Tpeak and Tpeak-to-Tend parameters from the ECG as potential proarrhythmia biomarkers, and the applicability of nonclinical concentration-QTc (C-QTc) modeling of data derived from the conduct of the in vivo QTc study as a component of the core battery of safety pharmacology studies.

Abstract 4649: BLX-3030, a potent, selective, orally available small molecule CDK9 inhibitor for aggressive variant prostate cancers

Abstract Background: The use of novel, potent targeted therapies in prostate cancers has led to the development of highly aggressive variant cancers, including neuroendocrine prostate cancer (NEPC). Gene amplification of N-MYC and C-MYC oncogenes leads to its overexpression in NEPC and mCRPC patients, highly prevalent in these lethal subtypes of cancers detected in 2% of all Prostate Cancers (PCa) and over 10-17% of mCRPC patients. N-MYC is a transcriptional target of CDK9, which acts as an oncogenic driver sufficient to transform human-derived prostate cancer to take on NEPC phenotypic changes resulting in a more aggressive disease identified in late-stage human PCa patients. Additionally, N-MYC and C-MYC are required for tumor drug resistance, and their downregulation through CDK9 inhibition lowers tumor growth. Our efforts have demonstrated that targeting both N-MYC and C-MYC as a driver of NEPC and mCRPC with highly selective CDK9 inhibitor BLX-3030 is a viable approach for therapeutic intervention of mCRPC and NEPC. Materials and Methods: Our empirical data-driven AI/ML MolecuLernTM fragment library, workflows, LigEdit design strategies, and hit2-lead optimization methods are employed. In vitro experiments include kinase glo, cell titer glo, selectivity profiler, ADME-Tox, FACS/apoptosis, cell migration, live cell imaging, immunofluorescent, western blot, combination studies and in vivo experiments including PK, prostate tumor models, 7-day tox, BLX-3030 non (GMP) scaleup and safety pharmacology experiments conducted. Results: We synthesized a series of novel small molecule CDK9 inhibitors that reversibly bind to CDK9, competitively block the ATP site with an IC50 of 1.06 nM, and elicit pharmacological responses in N-MYC, C-MYC, and other prostate cancer cells in vitro and in vivo. We studied the CDK9 N-MYC expression detected in PC-3, DU-145, LNCaP, and in LASCPC-01, NCI-H660, and 22RV1 cell lines. BLX-3030 exhibited potent cellular efficacy with an IC50 of 22 to 590 nM in PC cell lines and in N-MYC expressed cells had an activity of 76, 470, and 132 nM respectively, and reduced pCDK9, C-MYC, Mcl-1, N-MYC and its downstream RNA Pol II (Ser-2) and pAR (Ser-81) dose-dependently. BLX-3030 exhibits in vivo antitumor activity in LASCPC-01, 22RV1, and C4-2 prostate cancer mouse models. Several ADME-Tox, MTD, dose range finding, hERG and other in vivo safety pharmacology experiments have advanced BLX-3030 to the IND enabling studies. Conclusions: BLX-3030 is currently being investigated in non-clinical toxicology, toxicokinetic, and core battery of safety pharmacology studies including the assessment of effects on cardiovascular, central nervous, and respiratory systems. Citation Format: Zhaoang li, Chenyu Lin, Kyle Medley, Hariprasad Vankayalapati, David J. Bearss. BLX-3030, a potent, selective, orally available small molecule CDK9 inhibitor for aggressive variant prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4649.

Globalising innovation through co-inventions–the success case of the Korean lithium-ion battery industry

Radical innovations can shift the global competitiveness of entire nations. While countries typically struggle to absorb knowledge about novel technologies quickly, in which knowledge tends to be spatially sticky, an important exception is the fast catch-up of the Korean Li-ion battery industry from Japan in the early 2000s. In this paper, we conduct an exploratory case study on this surprising success story. Focussing on patent co-inventions between Korea and Japan, we investigate their significance, as well as underlying types of co-inventions and types of transferred knowledge. To this end, we proceed in four steps: (1) a Poisson regression model; (2) social network analyses; (3) patent inventor tracking and (4) patent coding. Our results indicate that Korean–Japanese co-inventions hold significantly greater influence than other cross-country co-inventions, including with patents without cross-country collaboration. We find a pronounced knowledge-transfer intensity during the early 2000s and observe two types of co-inventions: organisation-level and inventor-level. Predominantly, we observe inventor-level co-inventions, i.e. Korean companies hiring experienced Japanese engineers, that proved important to transferring sticky knowledge. Moreover, while most patents target the design of core battery components, the share of manufacturing patents are—contrary to theoretical expectations—highest during the first half of the observation period. We also discuss our findings and draw implications for policy, industrial and academic players, including industry localisation policies, technology-inherent catch-up strategies and directions for future research.

A tutorial for model-based evaluation and translation of cardiovascular safety in preclinical trials.

Assessment of drug-induced effects on the cardiovascular (CV) system remains a critical component of the drug discovery process enabling refinement of the therapeutic index. Predicting potential drug-related unintended CV effects in the preclinical stage is necessary for first-in-human dose selection and preclusion of adverse CV effects in the clinical stage. According to the current guidelines for small molecules, nonclinical CV safety assessment conducted via telemetry analyses should be included in the safety pharmacology core battery studies. However, the manual for quantitative evaluation of the CV safety signals in animals is available only for electrocardiogram parameters (i.e., QT interval assessment), not for hemodynamic parameters (i.e., heart rate, blood pressure, etc.). Various model-based approaches, including empirical pharmacokinetic-toxicodynamic analyses and systems pharmacology modeling could be used in the framework of telemetry data evaluation. In this tutorial, we provide a comprehensive workflow for the analysis of nonclinical CV safety on hemodynamic parameters with a sequential approach, highlight the challenges associated with the data, and propose respective solutions, complemented with a reproducible example. The work is aimed at helping researchers conduct model-based analyses of the CV safety in animals with subsequent translation of the effect to humans seamlessly and efficiently.

Simultaneous assessment of central nervous and respiratory systems using jacketed telemetry in socially-housed rats: Application of the “3Rs” principles in core battery safety pharmacology studies

Central nervous (CNS) and respiratory systems are routinely investigated in safety pharmacology core battery studies. For small molecules, the assessment of both vital organ systems is frequently done in rats in two distinct studies. With the advent of a miniaturized technology of jacketed external telemetry for rats (DECRO system), the simultaneous assessment of modified Irwin's or functional observational battery (FOB) test and respiratory (Resp) studies has become possible within a single study. Therefore, the objectives of this study were to perform the FOB and the Resp studies simultaneously in pair-housed rats fitted with jacketed telemetry, and to assess the feasibility and the outcome of this combination in control, baclofen, caffeine, and clonidine treated groups, i.e., with three agents having both respiratory and CNS effects. Our results provided evidence that performing both Resp and FOB assessment simultaneously in the same rat was feasible and the outcome was successful. The expected CNS and respiratory effects of the 3 reference compounds were accurately captured in each assay confirming the results' relevance. In addition, heart rate and activity level were recorded as additional parameters making this design as an enhanced approach for nonclinical safety assessment in rats. This work provides clear evidence that the “3Rs” principles can be effectively applied in core battery safety pharmacology studies while remaining in compliance with worldwide regulatory guidelines. Both reduction in animal use and refinements in procedures are demonstrated with this model.

Developing a Culturally Competent Neuropsychological Assessment Battery for Vietnamese-speaking Patients with Suspected Dementia.

To assemble a core battery of culturally and linguistically appropriate neuropsychological measures that can be administered to Vietnamese-speaking patients with suspected dementia. Test instruments in Vietnamese were identified through systematic searches of PubMed, PsychInfo, and Google Scholar, and in consultation with two Vietnamese-speaking cultural brokers. A battery assessing the domains of attention, executive function, verbal and visual episodic memory, basic language abilities, visuospatial/visuoconstruction abilities, and mood/anxiety was assembled that included core measures developed either specifically for a Vietnamese-speaking population, or were validated/normed with a Vietnamese-speaking sample either in Vietnam or Vietnamese-speaking persons in the U.S. Supplemental measures were selected that can be administered using translated instructions with U.S. English normative data. The rationale for test selection and caveats for their clinical use are presented. The number of neuropsychological measures identified in Vietnamese and/or with Vietnamese normative data was sparse. Given the large and growing population of Vietnamese-speaking residents in the U.S. and the aging of these communities, it is imperative to develop additional, appropriately designed and normed instruments to provide culturally competent assessments to better serve these individuals.

Test Review: Wechsler Individual Achievement Test, Fourth Edition (WIAT-4)

This article reviews the administrative, scoring, and psychometric properties of the Wechsler Individual Achievement Test, Fourth Edition (WIAT-4, NCS Pearson, 2020 ). The WIAT-4 is one of the more commonly administered broadband measures of academic achievement. The instrument was determined to be well-conceptualized, and generally psychometrically sound. Omissions include factor analyses to determine the instrument’s theoretical and scoring structure, and the lack of presentation of item analysis results. Importantly, the Essay Composition subtest is now much easier to score which should serve to increase interest in the WIAT-4 as a viable option for the assessment of academic achievement. Although there are a number of subtests beyond the core battery to administer, users may find that the time and effort required to administer those subtests are worth the effort given the rich detail furnished that is linked to scientific literature regarding the etiology of learning disabilities.

Non invasive jacketed telemetry in socially-housed rats for a combined assessment of respiratory system, electrocardiogram and activity using the DECRO system

Respiratory and cardiovascular systems are among the vital organ systems that should be studied in safety pharmacology core battery test. Non-invasive jacketed external telemetry technology that enables concomitant monitoring of both systems has been available and used widely for non-rodent species. Recently, the DECRO system, a miniaturized technology system in line with the “3Rs” principles, has been developed to provide a similar approach in rats. However, data to evaluate this system in socially-housed rats is lacking. Therefore, the objectives of this study were to determine the tolerability and the material integrity of this novel solution in pair-housed rats in two conditions: i) in a single session of 22 h simulating a stand-alone safety pharmacology study design, and ii) in three repeated sessions of 22 h each, simulating the inclusion of safety pharmacology endpoints in a 1-month toxicology study. In both conditions, the GABAB receptor agonist baclofen was used as a reference compound inducing cardiorespiratory changes. Our results provided evidence that this novel solution was well tolerated, the material was resistant to deterioration and that it allowed the accurate recording, in a non-invasive manner, of cardiorespiratory parameters and activity level in freely moving, pair-housed rats in the above two conditions. In addition, the expected respiratory depressant effects of baclofen were recorded. These results pave the way for considering this novel solution as an enhanced approach for nonclinical safety assessment in rats.

Thymidine Kinase+/- Mammalian Cell Mutagenicity Assays for Assessment of Nanomaterials.

The methods outlined here are part of a series of papers designed specifically for genotoxicity assessment of nanomaterials (NM). Common Considerations such as NM characterization, sample preparation and dose selection, relevant to all genotoxicity assays, are found in an accompanying paper. The present paper describes methods for evaluation of mutagenicity in the mammalian (mouse) thymidine kinase (Tk) gene occurring in L5178Y mouse lymphoma (ML) cells and in the designated TK gene in human lymphoblastoid TK6 cells. Mutations change the functional genotype from TK+/- to TK-/-, detectable as cells surviving on media selective for the lack of thymidine kinase (TK) function. Unlike cells with TK enzyme function, the TK-/- cells are unable to integrate the toxic selection agent, allowing these cells to survive as rare mutant colonies. The ML assay has been shown to detect a broad spectrum of genetic damage, including both small scale (point) mutations and chromosomal alterations. This assay is a widely used mammalian cell gene mutation assay for regulatory purposes and is included in the core battery of genotoxicity tests for regulatory decision-making. The TK6 assay is an assay using a human cell line derived similarly via mutagenic manipulations and optimal selection. Details are provided on the materials required, cell culture methods, selection of test chemical concentrations, cytotoxicity, treatment time, mutation expression, cloning, and data calculation and interpretation. The methods describe the microwell plate version of the assays without metabolic activation.

Preclinical evaluation of a plant-derived SARS-CoV-2 subunit vaccine: Protective efficacy, immunogenicity, safety, and toxicity

Coronavirus disease 2019 (COVID-19) is an acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The prevention of SARS-CoV-2 transmission has become a global priority. Previously, we showed that a protein subunit vaccine that was developed based on the fusion of the SARS-CoV-2 receptor-binding domain (RBD) to the Fc portion of human IgG1 (RBD-Fc), produced in Nicotiana benthamiana, and adjuvanted with alum, namely, Baiya SARS-CoV-2 Vax 1, induced potent immunological responses in both mice and cynomolgus monkeys. Hence, this study evaluated the protective efficacy, safety, and toxicity of Baiya SARS-CoV-2 Vax 1 in K18-hACE2 mice, monkeys and Wistar rats. Two doses of vaccine were administered three weeks apart on Days 0 and 21. The administration of the vaccine to K18-hACE2 mice reduced viral loads in the lungs and brains of the vaccinated animals and protected the mice against challenge with SARS-CoV-2. In monkeys, the results of safety pharmacology tests, general clinical observations, and a core battery of studies of three vital systems, namely, the central nervous, cardiovascular, and respiratory systems, did not reveal any safety concerns. The toxicology study of the vaccine in rats showed no vaccine-related pathological changes, and all the animals remained healthy under the conditions of this study. Furthermore, the vaccine did not cause any abnormal toxicity in rats and was clinically tolerated even at the highest tested concentration. In addition, general health status, body temperature, local toxicity at the administration site, hematology, and blood chemistry parameters were also monitored. Overall, this work presents the results of the first systematic study of the safety profile of a plant-derived vaccine, Baiya SARS-CoV-2 Vax 1; this approach can be considered a viable strategy for the development of vaccines against COVID-19.

Correlation between lower limb and trunk muscle endurance with drop vertical jump in the special military forces

Police officers, particularly the ones who are trained to be on "special forces", perform a wide range of hazardous and physically demanding activities when aiming to protect and serve. The purpose of this study was to investigate the association between lower limb and trunk muscle endurance with drop vertical jump (DVJ) height in a special military police force. One hundred and three male military men (age: 36±5.0 years; height: 1.76±0.05m; weight: 81.8±9.7kg) volunteered to take part in this study. DVJ, McGill core battery (trunk flexion, trunk extension, and side bridge test-right and left), and single-leg squat repetitions. Correlations were analyzed using the Pearson correlation coefficient (r). The level of significance for all analyses was set at p≤0.05. Single-leg squat repetitions were positively associated with DVJ height, contact time and flight time (p=0.00093∗∗, p= 0.00085∗∗, and p=0.00098∗∗ respectively). No correlation was observed between trunk muscle endurance and DVJ. Therefore, it was concluded that greater endurance of the lower limb muscles, as demonstrated by the single leg squat, was associated with better performance in a DVJ. Individuals should consider incorporating single leg squats into their fitness program to develop muscular endurance and possibly perform better in the DVJ.

STRUMM: An Intelligent, Adaptive Software Package for Older Adults With a Cognitive Impairment

Many older adults have a cognitive impairment (CI), which negatively impacts on their quality of life and threatens their independence. In this presentation, we provide an overview of the conceptual framework, structure, and processes of our multi-site Center, ENHANCE, which is focused on developing technology support for aging adults with a CI. ENHANCE has two cross-site research projects, two cross-site development projects, training, and dissemination components. A core battery of measures is collected across all projects. We also discuss the Supportive Technology Resources through Usability & Machine-learning Methods (STRUMM) research project, which focuses on an innovative intelligent adaptive software package aimed at providing cognitive and social support, and support for resource access to aging adults with a CI. STRUMM is designed to meet the user’s varying cognitive needs. Finally, we present preliminary data regarding the perceived usability and value of STRUMM from our clinical partners and potential user groups.

A-107 Quantifying the Effect of Sleepiness and Mood on Gross Neuropsychological Functioning in a Forensic Population with a History of Traumatic Brain Injury

Abstract Objective Traumatic brain injury (TBI) is a serious public health concern. Furthermore, inmates and probationers are at a higher risk for TBI, as well as mental health issues and sleepiness. Both sleep and mood disturbance have been linked to poor cognitive performance. These state-dependent cognitive changes can undermine the evaluation of true cognitive ability and contaminate validity. This study examined the effects of sleep and mood on neurocognitive functioning and its impact on the validity of assessment results. Methods This study looked at retrospective Automated Neuropsychological Assessment Metrics (ANAM) core battery data. The sample included inmates and probationers (n = 419) with a history of TBI. A multiple linear regression was used to examine the relationship between self-reported sleepiness, mood state, and cognitive performance. Results All regression models were statistically significant, with negative mood being the most significant predictor of ANAM throughput scores (p = 0.000). Higher endorsement of negative mood states was related to lower cognitive performance overall (p = 0.003). Sleepiness predicted worse performance on at the end of the battery (p < 0.05), whereas positive mood predicted better performance at the beginning of the battery (p < 0.01). Conslusion The present study confirms that negative mood adversely affects global neurocognitive test performance in a forensic population. Examiners should be aware that sleepiness and mood states have an effect on test performance during even brief cognitive batteries. The current findings suggest that it is imperative to screen and identify sleepiness and negative mood symptoms as they may depress test results and threaten the validity or test interpretations and recommendations.

Addiction Research Unit: Affective and cognitive mechanisms of specific Internet-use disorders.

In the eleventh International Classification of Diseases (ICD-11) of the World Health Organization, gambling disorder and gaming disorder are included in the category 'disorders due to addictive behaviours', which can be specified further as occurring either predominantly offline or predominantly online. Other specific problematic behaviours may be considered for the category 'other specified disorders due to addictive behaviours'. The Research Unit FOR 2974, funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), focuses on the most prominent online addictive behaviours: gaming, pornography use, buying-shopping and social-networks use. The main goal of the Research Unit is to contribute to a better understanding of the common and differential psychological as well as neurobiological mechanisms involved in these specific types of Internet-use disorders. We aim to investigate theoretically argued (bio)psychological processes with a focus on concepts coming from research of substance-use disorders, for example, cue reactivity and craving, executive functions and specific inhibitory control, coping, implicit cognitions, and decision making. One central characteristic of the Research Unit is that we will investigate all participants using a comprehensive core battery of experimental paradigms, neuropsychological tasks, questionnaires, biomarkers, ambulatory assessment, and a 6-month follow-up survey. Beyond the anticipated contributions to the scientific understanding of the mechanisms involved in the development and maintenance of respective online addictive behaviours, we also expect contributions to clinical practice by showing which affective and cognitive mechanisms may be addressed more intensively to optimize treatment.

High-performance electrospun membrane for lithium-ion batteries

Lithium-ion battery separator is one of the core battery components, owing to its assistance in ion migration and prohibiting electron transport inside the battery. Traditional separators made of polyolefin do not provide sufficient wettability to provide high energy density required for applications in high-end field. Although electrospun lithium ionized poly(ethylene-co-vinyl alcohol) (EVO-Li) membranes were considered earlier, their mechanical properties still appear to be inferior. In this work, the surface modification of EVO-Li membranes by poly-dopamine (PDA) with benzene structure and excellent adhesion ability to enhance their mechanical properties is reported. PDA was found to react with EVO-Li and form the C-N-O bonds, which further improved the ultimate tensile strength of the membrane. Simultaneously, its uptake property and thermostability were also improved.

124-LB: Development of IDG-16177, a Selective and Safe GPR40 Agonist for the Treatment of Type 2 Diabetes

GPR40 has been considered a potential therapeutic target for type 2 diabetes because activation of GPR40 stimulates insulin secretion when glucose levels increased. Fasiglifam, a GPR40 agonist, was withdrawn from clinical development in Phase III due to DILI. Therefore, we evaluated the safety profiles of IDG-16177, a novel GPR40 agonist. The potential for IDG-16177 to have off-target effects was assessed in a panel of 173 binding assays. 10 μM IDG-16177 demonstrated activity (>50% inhibition) against DP, EP2, EP3 and EP4 with 81, 83, 57 and 67 % inhibition, respectively. In a functional assay against the same targets, IDG-16177 was inactive in agonist and antagonist mode except for DP with 62.2% activity inhibition at a concentration of 10 μM. IDG-16177 and fasiglifam showed the similar level of hepatotoxic response in HμRELToxTM assay. Formation of reactive metabolite and covalent binding to proteins was evaluated in human hepatocytes. IDG-16177 shows lower covalent binding burden at expected human efficacious dose (0.3~1 mg) than fasiglifam. Transporter inhibitory potential of IDG-16177 was assessed in hepatic transporter-expressing membrane vesicles. IDG-16177 and fasiglifam showed the similar inhibition level of BSEP, MRP2, MRP3, and MRP4. But clinically predicted plasma concentration of IDG-16177 is lower than that of fasiglifam, so the safety margin of IDG-16177 is wider than that of fasiglifam. A core battery of safety pharmacology was evaluated and IDG-16177 did not induce adverse effect in all studies. A 4-week toxicity study was conducted in rats and monkeys, and the liver was determined as the target organ in monkeys. The NOAEL was over 60-fold than in vivo efficacy dose. IDG-16177 was not genotoxic in Ames test, in vitro and in vivo micronucleus test. And no phototoxicity was observed in in vitro 3T3 NRU study. These results shows that the potential for IDG-16177, a safe and effective GPR40 agonist, to treat patients with type 2 diabetes. Disclosure J. Yoon: None. J. Kim: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. J. Kim: None. S. Lee: None. C. Shin: None. Y. Jun: None. D. Hong: None. D. Lee: None. E. Jang: None.

Safety pharmacology of self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG), a novel siRNA nanoparticle platform.

The present safety pharmacology core battery studies (neurobehavior, respiratory, cardiovascular system, and human ether a-go-go (hERG) channel current) investigated the potential harmful effects of self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG). The SAMiRNA-AREG was administered by single intravenous injection at up to 300 mg/kg and 100 mg/kg in mice and monkeys, respectively. The hERG assay was performed in Chinese hamster ovary (CHO) cells at SAMiRNA-AREG concentrations of up to 200 μg/mL. In the evaluation on neurobehavior, a transient decrease in body temperature was found at 0.5 h (30 min) post-dose at both sexes in mice, with a single 300 mg/kg dose of SAMiRNA-AREG. However, these effects had returned to normal at 1 h post-dose. In the evaluation on hERG channel current, there were statistically significant differences in the inhibition of peak hERG potassium channel current between the 20, 100, and 200 μg/mL SAMiRNA-AREG treatment groups and the vehicle control group. However, these effects were less potent than that of E-4031, a positive control article. For the respiratory and cardiovascular systems, no treatment-related changes were observed in mice or monkeys. Thus, under these experimental conditions, these studies suggest that SAMiRNA-AREG showed no adverse effects on the neurobehavior, respiratory, and cardiovascular function.

Pennsylvania coordinated specialty care programs for first-episode psychosis: 6- and 12-month outcomes.

Pennsylvania (PA) first-episode psychosis (FEP) program evaluation is a statewide initiative, supported by the PA Office of Mental Health and Substance Abuse Services (PA-OMHSAS) and administered by PA Early Intervention Center/Heads Up, which evaluates fidelity and outcomes of PA Coordinated Specialty Care (CSC) programs. Programs participate in standard computerized measures of CSC outcomes using centralized informatics. The aims of the current report are to describe implementation of this core battery for program evaluation in PA and to present 6- and 12-month outcomes. Participants (n= 697) from nine PA CSC programs completed the core battery at admission. The battery was re-administered at 6- and 12-month follow-up, and data were analysed for individuals (n= 230) who had completed 12-months of treatment. Domains assessed via clinician report and/or self-report included symptoms, role and social functioning, self-perceived recovery and service utilization. PA FEP CSC participants showed improvement over time in several domains, including decreased symptoms, higher role and social functioning, decreased hospitalizations, and improved self-perception of recovery, quality of life, and services satisfaction. Trends towards improvements were observed for participant happiness, hopelessness, and school-enrolment. Nearly all improvements were observed at 6-month follow-up, with earlier gains maintained at 12-months. PA FEP CSC programs demonstrate the ability to assess and improve critical outcomes of coordinated specialty care in PA. Improved outcomes by 12 months in treatment provides evidence of an effective treatment model and supports the continuation of these programs in pursuit of our goal of reducing schizophrenia disease burden on individuals and society.