Safety Pharmacology Research Articles

Abstract 5710: The brain penetrant CDK4/6 inhibitor, PRT3645, is highly effective in combination with other targeted therapies in preclinical models of breast cancer, CRC and NSCLC

Abstract Cell cycle deregulation is a hallmark of cancer and the hyperactivation and overexpression of cyclin-dependent kinase (CDK)s are often drivers of cancer pathogenesis. CDK4/6 are critical mediators of cellular transition into S phase and important for cancer initiation, growth, and survival. Previously we reported a novel brain penetrant CDK4/6 inhibitor, PRT3645, that exhibits single digit nanomolar biochemical potency against CDK4/6 and >2000-fold selectivity against other CDKs. PRT3645 inhibits cellular phosphorylation of Rb with nanomolar potency. Furthermore, PRT3645 exhibits favorable in-vivo safety pharmacology and ADME properties, including increased brain penetration, and demonstrates oral bioavailability across rodents, dog and non-human primates. Here, we explored the therapeutic potential of PRT3645 in tumor models harboring actionable genomic alterations but lacking effective targeted treatments. Specifically, we explored the combination of PRT3645 with a selective estrogen receptor degrader (SERD), an approved treatment for patients with HR+/HER2-, ESR1-mutated advanced or metastatic breast cancer. In an ESR1 mutated breast cancer PDX model, PRT3645 not only exhibited monotherapy activity but also induced significant tumor regression in combination with a SERD through inhibiting ER-mediated signaling. We also investigated PRT3645 single agent activity and combination with a clinically validated MEK inhibitor in a BRAF class III mutant colorectal CDX model. PRT3645 was well-tolerated and demonstrated significant anti-tumor efficacy, which was further enhanced by combination therapy. To further explore comprehensive inhibition of cell cycle progression and overcome potential resistance to CDK4/6 inhibition, we investigated dual inhibition of CDK4/6 and CDK2. CDK2 is a crucial player in regulating the cell cycle by controlling the late G1/S transition, promoting DNA replication, and contributing to the DNA repair processes. Additionally, CDK2 activation has been identified as a potential mechanism of resistance to CDK4/6 inhibition. We evaluated CDK2 and CDK4/6 dual inhibition in CDKN2A loss or CCNE amplified cancer cell lines and observed enhanced proliferation suppression, cell cycle arrest and senescence induction, underscoring the potential of this combination for improved therapeutic efficacy across various cancer types. In summary, PRT3645 displays an excellent balance of potency, selectivity, pharmacokinetic parameters across species as well as brain penetrance. In preclinical studies, PRT3645 was highly efficacious when combined with other targeted therapies, offering potential benefits across a wide spectrum of cancer types. In addition, the concept of dual inhibition of CDK4/6 and CDK2 presents a rational and promising approach to enhance the efficacy of cancer therapy. Citation Format: Yue Zou, Kirsten Gallagher, Srijita Dhar, Andrew Busking, Sarah Pawley, Ryan Holmes, Xiaowei Wu, Min Wang, Joseph Rager, Tom Emm, Stefan Ruepp, Miles Cowart, Andrew Combs, Kris Vaddi, Sandy Geeganage, Peggy Scherle, Sang Hyun Lee. The brain penetrant CDK4/6 inhibitor, PRT3645, is highly effective in combination with other targeted therapies in preclinical models of breast cancer, CRC and NSCLC [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 5710.

Abstract 1661: Preclinical characterization of HMPL-295, a potent and selective ERK 1/2 inhibitor

Abstract Background: Although therapeutic agents targeting alterations in the MAPK pathway have achieved great clinical success, the overall benefit is still suboptimal. Several studies have shown that reactivation of MAPK signaling is the main basis to compromise the efficacy. Thus, co-inhibition of ERK, the terminal master kinase of MAPK pathway, and the upstream targets may effectively shut down the MAPK signaling cascade and induce deeper and more durable anti-tumor activities. Herein, we present the preclinical characterization of HMPL-295, a potent and selective ERK 1/2 inhibitor, discovered and being currently developed in phase I clinical trial (NCT04908046) by HUTCHMED. Methods: The inhibition on ERK 1/2 kinase was determined using Z-LYTE™ kinase assay. The selectivity of HMPL-295 was evaluated against 394 kinases (KinaseProfilerTM) and 86 safety-related proteins (SafetyScreen87TM) by Eurofins. Cellular target inhibition on phosphorylation of RSK (p-RSK) was detected by ELISA. In vitro anti-proliferation activity of HMPL-295 as a single agent was measured by CCK-8 or CellTiter-Glo luminescent assay. Colony formation assay was used to evaluate the combination effect of HMPL-295 with targeted therapy. Multiple tumor models with RAS/RAF/MAPK pathway activation were applied in immune-deficient mice to investigate the anti-tumor activity of HMPL-295 as a single agent or in combination with either chemotherapy or targeted therapy. Results: HMPL-295 strongly inhibited ERK1 and ERK2 kinase activities with equal IC50 at 4 nM. In human colon cancer cell line COLO 205 harboring BRAFV600E mutation, HMPL-295 inhibited p-RSK, a direct substrate of ERK1/2, with an average IC50 of 180 nM from 3 independent experiments. With the inhibition of ERK and its downstream substrates, HMPL-295 treatment induced tumor cells arresting at G0/G1 phase via down-regulation of cyclin D1/p-RB signaling and consequently attenuated cell growth in a panel of MAPK pathway dysregulated tumor cell lines, but barely affected the growth of normal cells. Furthermore, HMPL-295 demonstrated favorable selectivity in the kinase and safety pharmacology profiling, indicating a low off-target risk. For in vivo studies, oral administration of HMPL-295 induced time- and dose-dependent inhibition of p-RSK and resulted in dose-dependent anti-tumor activity in several tumor models harboring KRAS or BRAF mutations. Moreover, HMPL-295 significantly improved the anti-tumor activity of standard-of-care chemotherapy as well as targeted agents in KRAS- or BRAF-mutant tumor models both in vitro and in vivo. Conclusion: HMPL-295 is a potent and selective ERK1/2 inhibitor which demonstrates strong anti-tumor activity in preclinical models, supporting further clinical evaluation. Citation Format: Jia Hu, Jun Ni, Yuanzhi Lv, Wenjun Li, Hui Zhang, Xin Li, Ying Yu, Zeyu Zhong, Jian Wang, Yang Sai, Weiguo Qing, Yongxin Ren, Michael Shi, Weiguo Su. Preclinical characterization of HMPL-295, a potent and selective ERK 1/2 inhibitor [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 1661.

Abstract 4501: First reported PIM kinase degraders: Design, profiling & optimization

Abstract The PIM serine/threonine kinases (PIM1/PIM2/PIM3) are downstream effectors of ABL, JAK2 and Flt-3 oncogenes and are required for tumorigenesis. Overexpression has been reported in hematological and solid tumors, myeloma, lymphoma, leukemia and adenocarcinoma. The first generation of PIM inhibitors to make it to the clinic, including SGI-1776, AZD1208 and PIM447, are known to be pan-PIM inhibitors, while the aim of this project was to identify novel & selective PIM3 inhibitors. To this end, several Hit-finding approaches were employed to rapidly generate novel chemical matter, which were then assessed for their activity against PIM3 using a robust ADP-Glo™ assay. In parallel to this Hit-findings activity, we used AZD1208 scaffold as a starting point to generate PIM3 bifunctional protein degraders and designed a specific screening cascade in order to profile such modalities. The PIM degrader library, synthetized using Automated Robotics Lab, was characterized using ADP-Glo assays. It was then screened on our binding and activity kinase platforms, KINOMEscan® and KinaseProfiler™, and then fully profiled including ternary complex formation with biophysics and in vitro Safety Pharmacology Profiling Panels. One example is the AZD1208 derivate degrader, i.e. EC108154-1, which showed nanomolar range affinity for PIM3 and the E3-ligase CRBN-DDB1, and its affinity range was also confirmed with the ternary complex in SPR and MST-TRIC. This comprehensive screening cascade ensures an in-depth characterization and optimization of protein degraders, with the possibility of monitoring the ternary complex formation with biophysics methods. It is a good illustration of how this combination of tests can be instrumental in selecting the best degraders to progress to the next step of drug discovery. Citation Format: Celine Legros, Paul Ratcliffe, Vanessa Porkolab, Michele Modugno, Olivier Mirguet. First reported PIM kinase degraders: Design, profiling & optimization [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 4501.

Abstract 3315: Preclinical studies of TSN1611, a potent, selective, and orally bioavailable KRASG12D inhibitor

Abstract Background: KRAS mutations are the most frequently encountered driver oncogene, involved in ~25% of all human cancers [1,2]. KRASG12D is the predominant KRAS mutation isoform, detected in approximately 35% of pancreatic cancer, 13% of colorectal cancer, and 5% of NSCLC [3]. Compared to KRASG12C, targeting KRASG12D has proven to be more challenging since the target protein lacks a reactive amino acid residue for irreversible inhibitory modification by a ligand. Herein, we disclose TSN1611, a potent and selective KRASG12D inhibitor, which possesses favorable oral PK profiles and demonstrates significant in vitro and in vivo anti-tumor activity in various KRASG12D-mutant models. Method: Biochemical HTRF assay was used to measure the inhibition of TSN1611 to both GDP-bound and GTP-bound state of KRASG12D. Biophysical SPR method was used to directly measure the binding of TSN1611 to GDP-bound KRASG12D and KRASWT. Cell based activities were evaluated in a series of in vitro cell proliferation assay utilizing Ba/F3 cells engineered with KRASG12D or non-KRASG12D mutations and tumor cell lines harboring KRASG12D mutation. Human cancer cell-derived xenograft models of HPAC (pancreatic) and GP2D (colorectal) were used to evaluate its in vivo antitumor effect. in vitro and in vivo PK studies were performed in mouse, rat, and dog. Systematic nonclinical safety evaluations, including safety panel screen testing, safety pharmacology studies, and repeat-dose toxicity studies were carried out to assess its preliminary toxicity profile. Results: TSN1611 inhibited both active (GTP-bound) and inactive (GDP-bound) forms of KRASG12D protein at IC50 1.23 and 1.49 nM, respectively; the KD value of its direct binding to KRASG12D protein is 1.93 pM in SPR assay. TSN1611 demonstrated potent anti-proliferation activity against several tumor cell lines harboring KRASG12D mutation, and excellent selectivity over cells of NRAS, HRAS, and other KRAS isoforms. It also showed dose-dependent anti-tumor efficacy in GP2D and HPAC models. Mechanism of action studies concluded that the antitumor effect of TSN1611 is resulted from its effective inhibition of KRAS signaling pathway. Oral bioavailability and safety profile across multiple species supported its further development. Conclusion: TSN1611 is a selective KRASG12D inhibitor. It exhibited excellent selectivity and activity both in vitro and in vivo; it demonstrated favorable physicochemical properties, oral PK profiles, and brain penetration potential; it also showed acceptable margins of safety. The preclinical data supports further development. Pending regulatory submission and review, the phase I/II study is planned to start in H1 of 2024.

Micro-Engineered Heart Tissues On-Chip with Heterotypic Cell Composition Display Self-Organization and Improved Cardiac Function.

Advanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety pharmacology. Conventional3DEngineered Heart Tissues (EHTs) lack heterotypic cell complexity and culture under flow, whereas microfluidic Heart-on-Chip (HoC) models in general lack the 3D configuration and accurate contractile readouts. In this study, an innovative and user-friendly HoC model is developed to overcome these limitations, by culturing human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs), endothelial (ECs)- and smooth muscle cells (SMCs), together with human cardiac fibroblasts (FBs), underflow, leading to self-organized miniaturized micro-EHTs (µEHTs) with a CM-EC interface reminiscent of the physiological capillary lining. µEHTs cultured under flow display enhanced contractile performance and conduction velocity. In addition, the presence of the EC layer altered drug responses in µEHT contraction. This observation suggests a potential barrier-like function of ECs, which may affect the availability of drugs to the CMs. These cardiac models with increased physiological complexity, will pave the way to screen for therapeutic targets and predict drug efficacy.

Methods of mathematical planning of the experiment and their use in the development of the composition of the ointment with essential oil thymus vulgaris l. For vaginal application

One of the most important pharmaceutical factors is excipients, their nature and quantity, which increase the pharmacological activity and safety of APIs by creating dosage forms that are optimal in composition, properties, and type, and/or by changing the chemical modification of the molecule responsible for the pharmacological effect of the active substance. Variability or variation in the number of excipients and the use of different excipients with the same intended functionality can complicate the release rate and bioavailability of drugs. The use of mathematical methods at the stage of the experiment planning reduces the total number of experiments and at the same time provides reliable results. Aim. To study the most used types of mathematical planning of the experiment, and select the most acceptable model for developing the optimal composition of a vaginal ointment with the thyme (Thymus vulgaris L.) essential oil. Results and discussions. To develop the optimal composition of the ointment, 10 bases containing various excipients (factor A) and 6 excipients as an emulsifier (factor B) were used. The concentration of the thyme essential oil was 5 % in all samples. The degree of thymol release in the in vitro study using the equilibrium dialysis method was chosen as the criterion for choosing the optimal composition. The selection of excipients for the development of a soft dosage form was carried out using the method of the a priori ranking since both bases and emulsifiers were selected as the most widely used in the pharmaceutical technology, with known characteristics, safety profile, application experience. Conclusions. The degree of influence of each factor has been determined, and the series of Duncan’s test have been constructed for each factor – by factor a: а3 > а5 > а4 > а6 > а2 > а8 > а7 > а10 > а9> а1, and by factor b: b2 > b3 > b5 > b4 > b6 > b1. Based on the mathematical planning of the experiment, an ointment base and an emulsifier for developing the composition of a vaginal gel with the thyme oil have been determine.

Extraction, Paper and Thin layer Chromatography and activity of Curcumin

Curcumin is extensively cultivated as spices and herbal medicines in tropical and sub-tropical countries. Geographical origin is known to significantly determine the quality of the herbs used and, consequently, the safety and efficacy of their products. Curcumin is commercially available as a nutrition supplement as it exhibits various medicinal and nutritional properties. Its essential oil is present upto 7%; with high content of bisabolane derivatives. Curcumin has shown potent antibacterial activity and other pharmacological actions in the past 50 years. Curcumin has been marketed globally as a health supplement mainly for its antioxidant and anti-inflammatory, antibacterial properties. Curcumin possesses antibacterial activity against periodontopathic bacteria and may be a potent agent for preventing periodontal diseases. Possession of useful properties, pharmacological safety and negligible cost make curcumin an attractive agent to explore further for its potential therapeutic applications in various endodontic procedures.

Adjuvant Activity and Toxicological Risks of Lipid Nanoparticles Contained in the COVID‑19 “mRNA Vaccines”

The LNPs reportedly used as the platform by Pfizer/BioNTech for its SARS-CoV-2 “mRNA vaccines” allegedly consist of a mixture of phospholipids, cholesterol, PEGylated lipids, and an ionizable cationic lipid. This study reviews some of the main toxicological risks and immunostimulatory properties of such nanomaterials, with particular attention to the ionizable LNPs and their adjuvant properties, inflammatory responses, stimulation of immune cells, and formation of ROS inside transfected cells. The decision not to carry out safety pharmacology, carcinogenicity, and genotoxicity tests on these nanomaterials appears unjustifiable and in contradiction with the international policies provided for novel adjuvants. Important gaps are highlighted on the activities by the relevant regulatory bodies, related to the scientific evaluation, risk management, and pharmacovigilance for new medicinal products in the EU. Given the findings discussed here, it is strongly urged that the mRNA-LNP-based “vaccines” and their boosters should be removed from the worldwide market because of unacceptable and potentially fatal safety risks.

Pre-clinical Efficacy and Safety Pharmacology of PEGylated Recombinant Human Endostatin.

This study aimed to outline the pre-clinical efficacy and safety pharmacology of PEGylated recombinant human endostatin (M2ES) according to the requirements of new drug application. The purity of M2ES was evaluated by using silver staining. Transwell migration assay was applied to detect the bioactivity of M2ES in vitro. The antitumor efficacy of M2ES was evaluated in an athymic nude mouse xenograft model of pancreatic cancer (Panc-1) and gastric cancer (MNK45). BALB/C mice were treated with different doses of M2ES (6, 12 and 24 mg/kg) intravenously, both autonomic activity and cooperative sleep were monitored before and after drug administration. The apparent molecular weight of M2ES was about 50 kDa, and the purity was greater than 98%. Compared with the control group, M2ES significantly inhibits human micro-vascular endothelial cells (HMECs) migration in vitro. Notably, weekly administration of M2ES showed a significant antitumor efficacy when compared with the control group. Treatment of M2ES (24mg/kg or below) showed no obvious effect on both autonomic activity and hypnosis. On the basis of the pre-clinical efficacy and safety pharmacology data of M2ES, M2ES can be authorized to carry out further clinical studies.

Hotspots and frontiers in Helicobacter pylori biofilm research: A bibliometric and visualization analysis from 1998 to 2023

BackgroundHelicobacterpylori (H. pylori) biofilm formation is a key factor in refractory H. pylori infection. The aim of this study was to understand research trends in H. pylori biofilms. MethodsThe Web of Science Core Collection database was used to retrieve publications published from 1998 to 2023. Different kinds of software, EXCEL, an online bibliometric analysis platform, and the VOS viewer were used to evaluate and visualize the bibliometric data. ResultsIn total, 184 publications were identified, and the number of publications increased annually. The USA made the greatest contributions to this research field, while Helicobacter was the most productive journal. Grande rossella published the most papers, and the most productive institution was Gabriele D'Annunzio university. Co-occurrence network maps revealed that the keyword “Helicobacter pylori” ranked first in research field, and the keyword of “biofilm formation” and “in vitro” began to appear in the past three to five years. The majority of the five most-cited articles (60%) were published in USA and focused on the mechanism of H. pylori biofilm formation. ConclusionThe annual number of publications on H. pylori biofilms has increased steadily over the past two decades and will continue to increase. Future studies should focus on evaluate the pharmacological effects, efficacy and safety of these anti-biofilm treatments in animal models and clinical trials.

Disposition Kinetics and Tissue Distribution of Titanium Dioxide (TiO<sub>2</Sub>) Nanoparticles Following Single Exposure in Male Wistar Rats

Titanium Dioxide (TiO2) nanoparticles are one among the several environmental contaminants essentially due to their widespread applications in food, medicine, cosmetics, electronics, and several other applications. The current experimental study was undertaken to determine the toxicokinetic variables and tissue distribution profile of titanium (Ti) following single intraperitoneal (i.p) administration of titanium dioxide nanoparticles (TiO2 NPs) in male Wistar rats. The Tmax(obs.), Cmax (obs.), the elimination half-life (t1/2k10), the area under the curve (AUC0-336), and AUC0-∞ of TiO2 following single i.p administration of TiO2 NPs in whole blood was 0.5h, 0.26 ± 0.03 μg.ml-l, 486.31 ± 39.66 h, 48.81 ± 0.54 μg/ml*h and 128.28 ± 7.17 μg/ml*h, respectively. The mean Titanium (Ti) concentration ratio for tissue(s)- to whole blood measured at 336 h as well as the Cmax(obs.) was in the order of liver > spleen > lung > kidney > testis > brain following single i.p administration. The elimination half-life (t1/2k10) was in the order of spleen > kidney > liver > lung. The toxicokinetic and tissue distribution profile TiO2 NPs thus derived would serve as baseline data to execute long-term studies with toxicoepidemiological relevant concentration so as to re-visit safety pharmacology governing TiO2 -nanoparticles exposure from various sources including pharmaceuticals.

Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor.

Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50's ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue.

Ligand based-design of potential schistosomiasis inhibitors through QSAR, homology modeling, molecular dynamics, pharmacokinetics, and DFT studies

ObjectivesSchistosomiasis, a neglected tropical disease, is a leading cause of mortality in affected geographic areas. Currently, because no vaccine for schistosomiasis is available, control measures rely on widespread administration of the drug praziquantel (PZQ). The mass administration of PZQ has prompted concerns regarding the emergence of drug resistance. Therefore, new therapeutic targets and potential compounds are necessary to combat schistosomiasis. MethodsTwenty-four potent derivatives of PZQ were optimized via density functional theory (DFT) at the B3LYP/6-31G∗ level. Quantitative structureactivity relationship (QSAR) models were generated and statistically validated, and a lead candidate was selected to develop therapeutic options with improved efficacy against schistosomiasis. The biological and binding energies of the designed compounds were evaluated. In addition, molecular dynamics; drug-likeness; absorption, distribution, metabolism, excretion, and toxicity (ADMET); and DFT studies were performed on the newly designed compounds. ResultsFive QSAR models were generated, among which model 1 had favorable validation parameters (R2train: 0.957, R2adj: 0.941, LOF: 0.101, Q2cv: 0.906, and R2test: 0.783) and was chosen to identify a lead candidate. Other statistical parameters for the chosen model included variance inflation factor values ranging from 1.242 to 1.678, and a Y-scrambling coefficient (cRp2) of 0.747. Five new compounds were designed with improved predicted activity (ranging from 5.081 to 7.022) surpassing those of both the lead compound and PZQ (predicted pEC50 of 5.545). Molecular dynamics simulation revealed high binding affinity of the proposed compounds toward the target receptor. ADMET and drug-likeness assessments indicated adherence to Lipinski's rule of five criteria, thereby suggesting pharmacological and oral safety. In addition, DFT analysis indicated resistance to electronic alteration during chemical reactions. ConclusionThe proposed compounds exhibited potential drug characteristics, thus indicating their suitability for further investigation to enhance schistosomiasis treatment options.

From genes to drugs: CYP2C19 and pharmacogenetics in clinical practice.

The CYP2C19 gene is frequently included in different pharmacogenomic panels tested in clinical practice, due to its involvement in the metabolism of a myriad of frequently prescribed medications. Accordingly, CYP2C19 genotyping can promote precise therapeutic decisions and avoid the occurrence of significant drug-drug-gene interactions in the clinical setting. A comprehensive examination of the role of the CYP2C19 gene in real-world medical settings is presented in this review. This review summarizes the most recent information on how genetic variants in CYP2C19 affect drug metabolism and therapeutic outcomes. It goes into the wide range of CYP2C19 phenotypes, with different degrees of metabolizing activity, and their implications for customized medication response through a review of the literature. The review also analyzes the clinical significance of CYP2C19 in several medical specialties, including cardiology, psychiatry, and gastro-enterology clinics, and illuminates how it affects pharmacological efficacy, safety, and adverse effects. Finally, CYP2C19-supported clinical decision-making is outlined, highlighting the possibility of improving therapeutic outcomes and achieving more affordable treatment options, a step towards optimizing healthcare provision through precision medicine.

Studying the pharmacological safety of the standardized cleared bischofit brine

In experiments on mature rats, the pharmacological safety of a purified form of a standardized brine of the mineral bischofite (SBB) was assessed with repeated intragastric administration for 90 days at a dose of 0.01 ml/kg (experimentally proven therapeutic dose). It has been established that the test substance does not have a damaging effect on the general condition of animals (body weight, coat and skin, behavior), hematological and biochemical blood parameters, electrophysiological work of the myocardium, liver and kidney function, does not contribute to changes in the morphostructure of internal organs and brain. In the action of SBB with repeated 90-day administration, the effects of gender differences in behavioral activity (increase in motor and emotional activity in males and decrease in such effects in females) were revealed, electrocardiogram (increased heart rate and amplitude of the "R" wave in males and no changes in females), biochemical parameters (increased glucose levels in males and no changes in females). These changes did not go beyond the physiological norm and completely leveled to the state of control during the 30-day withdrawal of SRP administration.

Emerging Technologies and Advanced Biomarkers for Enhanced Toxicity Prediction and Safety Pharmacology

Background: Biomarkers are important tools in toxicology that can improve risk assessment, early detection of organ injury, and monitoring of pharmacological responses. However, rigorous validation is necessary to justify use for regulatory decisionmaking. Purpose: This article reviews the current landscape surrounding established and emerging biomarkers of toxicity across multiple techniques, with a focus on assessment of merits, limitations, and validation needs. Main Body: An overview of common clinical chemistry biomarkers used for safety monitoring of liver, kidney, heart, and inflammation is first provided, highlighting their biological relevance and applications in detecting organ dysfunction. Novel protein biomarkers emerging for enhanced sensitivity of injury detection are then discussed, such as microRNAs for liver and clusterin for kidney. Metabolomic biomarker approaches to assess biofluids and mitochondrial toxicity are outlined, along with toxicogenomic markers of susceptibility like HLA alleles. Non-invasive imaging techniques including ultrasound, MRI, and PET tracers for organ function are explored as techniques that provide additional modalities for biomarker measurement. Emerging tools like organ microphysiological systems and high-throughput omics for biomarker discovery are also described. Conclusion: While great progress has been made, translation and qualification of novel biomarkers remains challenging. This review synthesizes key developments across biomarker categories, evaluates readiness for regulatory use, and outlines strategic considerations for fit-for-purpose biomarker validation to advance integration into drug development programs.

DTox: A deep neural network-based in visio lens for large scale toxicogenomics data.

With the advancement of large-scale omics technologies, particularly transcriptomics data sets on drug and treatment response repositories available in public domain, toxicogenomics has emerged as a key field in safety pharmacology and chemical risk assessment. Traditional statistics-based bioinformatics analysis poses challenges in its application across multidimensional toxicogenomic data, including administration time, dosage, and gene expression levels. Motivated by the visual inspection workflow of field experts to augment their efficiency of screening significant genes to derive meaningful insights, together with the ability of deep neural architectures to learn the image signals, we developed DTox, a deep neural network-based in visio approach. Using the Percellome toxicogenomics database, instead of utilizing the numerical gene expression values of the transcripts (gene probes of the microarray) for dose-time combinations, DTox learned the image representation of 3D surface plots of distinct time and dosage data points to train the classifier on the experts' labels of gene probe significance. DTox outperformed statistical threshold-based bioinformatics and machine learning approaches based on numerical expression values. This result shows the ability of image-driven neural networks to overcome the limitations of classical numeric value-based approaches. Further, by augmenting the model with explainability modules, our study showed the potential to reveal the visual analysis process of human experts in toxicogenomics through the model weights. While the current work demonstrates the application of the DTox model in toxicogenomic studies, it can be further generalized as an in visio approach for multi-dimensional numeric data with applications in various fields in medical data sciences.

Safety pharmacology of acute psilocybin administration in healthy participants

Psilocybin is being studied for its therapeutic potential in various mental health disorders, such as depression, anxiety, and addiction. Initial studies suggested that psilocybin is generally safe when used under controlled conditions, but more research is needed to better understand its safety profile. We report safety pharmacology data from a pooled analysis of three randomized crossover studies that included 85 healthy participants and 113 single-dose administrations of psilocybin. Single oral doses included 15 mg, 20 mg, 25 mg, and 30 mg psilocybin dihydrate. We investigated subjective effects, blood pressure, heart rate, body temperature, acute and subacute adverse effects, reports of flashbacks, and liver and kidney function before and after the studies. The 20, 25, and 30 mg doses of psilocybin produced stronger effects than the 15 mg dose. Psilocybin at all doses induced higher “good drug effects” than “bad drug effects.” Only the 25 and 30 mg doses increased anxiety. Psilocybin elevated autonomic effects only moderately. Tachycardia (>100 beats/min) was observed with 7% of all psilocybin administrations. Body temperature >38° was reached in 7%, 9%, 17%, and 32% of the participants with the 15, 20, 25, and 30 mg doses, respectively. Kidney and liver function parameters were unaltered at the end of the study. Five participants (6%) reported transient flashback phenomena. No serious adverse reactions occurred. These findings suggest that a single administration of psilocybin is safe with regard to acute psychological and physical harm in healthy participants in a controlled research setting.

A comprehensive review of the use of lemborexant in treating insomnia

Abstract Lemborexant (LEM), a dual orexin receptor antagonist, represents a significant advancement in treating insomnia, a prevalent sleep disorder affecting a considerable portion of the population, especially older adults in India. LEM has several benefits over conventional sedatives in the treatment of insomnia, such as the selective mechanism of action, lower risk of tolerance and dependence, better sleep architecture, reduced possibility of cognitive impairment, various dosing options, the risk of rebound insomnia, and the risk of drug–drug interactions are also decreased. This thorough examination explores the pharmacological mechanisms, pharmacokinetics, clinical effectiveness, and safety profile of LEM, providing valuable insights into its distinct mode of action compared with traditional medications targeting gamma-aminobutyric acid receptors. By blocking orexin receptors (orexin 1 receptor and orexin 2 receptor), LEM regulates neuropeptides orexin A and orexin B, crucial for controlling wakefulness and arousal. Clinical trials demonstrate its predictable pharmacokinetics, dose-dependent effects, and minimal adverse reactions, confirming its efficacy in improving sleep initiation and maintenance. Long-term studies on LEM’s sustained therapeutic benefits show no signs of rebound insomnia or withdrawal. Its favorable safety profile, including minimal impact on next-day functioning, cognitive abilities, and postural stability, sets it apart from other treatments. The exploration of potential drug interactions underscores the importance of cautious prescribing, especially concerning cytochrome P450 3A inhibitors and inducers. As LEM becomes integrated into healthcare protocols, it promises to be a well-tolerated and effective solution, reshaping standard treatment approaches for insomnia and overcoming the limitations of older medications. In summary, LEM is a valuable addition to the pharmacotherapeutic toolbox, offering a novel strategy for managing sleep disturbances with sustained efficacy and favorable safety features.

Trabectedin may be a valuable treatment option for elderly patients with metastatic soft tissue sarcomas.

In the landscape of metastatic soft tissue sarcoma (mSTS) treatment, anthracyclines have shown efficacy; however, their associated toxicity imposes significant limitations, especially in frail elderly patients with mSTS who are highly susceptible to severe adverse effects. In this context, trabectedin, due to its distinct pharmacological profile and safety profile, may represent an interesting alternative being demonstrated to be active in treating mSTS. These features hold particular significance for elderly and unfit patients with mSTS, where balancing treatment benefits with potential adverse effects represents the pivotal objective. The investigation was focused on a specific group of 11 elderly patients with mSTS aged ≥70, all undergoing first-line treatment with trabectedin, and it was supported by comprehensive pharmacokinetic and pharmacodynamic studies. Among these patients, 9 out of 11 started the treatment at a dose of 1.5 mg/m2. The primary objective of this investigation is to highlight trabectedin as a valuable first-line treatment option for elderly and unfit patients with mSTS. Additionally, this investigation seeks to explore whether higher administered doses of trabectedin can enhance clinical outcomes while maintaining the same toxicity profiles. The median progression-free survival (PFS) was 77 days (95% CI, 53-89), the median overall survival (OS) was 397 days (95% CI, 66-2,102), while the overall toxicity of grade 3-4 severity amounted to 43%. These findings provide new insights into the clinical outcomes and toxicity associated with trabectedin in an elderly patient population, enhancing our understanding of better treatment approaches for a specific population of patients with mSTS.