Alimemazine 15mg/5ml oral solution

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells using angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP-1) as the primary receptor and entry co-factor, respectively. Cell entry is the first and major step in initiation of the viral life cycle, representing an ideal target for antiviral interventions. In this study, we used a recombinant replication-deficient vesicular stomatitis virus-based pseudovirus bearing the spike protein of SARS-CoV-2 (SARS2-S) to screen a US Food and Drug Administration-approved drug library and identify inhibitors of SARS-CoV-2 cell entry. The screen identified 24 compounds as primary hits, and the largest therapeutic target group formed by these primary hits was composed of seven dopamine receptor D2 (DRD2) antagonists. Cell-based and biochemical assays revealed that the DRD2 antagonists inhibited both fusion activity and the binding of SARS2-S to NRP-1, but not its binding to ACE2. On the basis of structural similarity to the seven identified DRD2 antagonists, which included six phenothiazines, we examined the anti-SARS-CoV-2 activity of an additional 15 phenothiazines and found that all the tested phenothiazines shared an ability to inhibit SARS2-S-mediated cell entry. One of the phenothiazines, alimemazine, which had the lowest 50% effective concentration of the tested phenothiazines, exhibited a clear inhibitory effect on SARS2-S-NRP-1 binding and SARS-CoV-2 multiplication in cultured cells but not in a mouse infection model. Our findings provide a basis for the development of novel anti-SARS-CoV-2 therapeutics that interfere with SARS2-S binding to NRP-1.

Abstract licence: CC BY

This study introduces an oxidative derivatization procedure enabling the indirect spectrofluorometric assessment of alimemazine tartrate (ALZ). ALZ was derivatized using potassium hydrogen peroxomonosulphate (Oxone®) to yield a strongly fluorescent sulfoxide. A fast, simple, and highly sensitive fluorescence method for ALZ tartrate determination was developed based on the emission from its oxone-oxidized product in 0.05 M sulfuric acid (λex = 340 nm; λem = 380 nm). The calibration curve displayed linearity across the concentration range of 0.1–13.5 μg/mL, and the LOQ (10S) was 0.42 μg/mL, demonstrating the potential for a quantitative assay in pharmaceutical formulations, such as the film-coated tablets Theralen® 5 mg and Teraligen® 5 mg, Theralen® 4% oral drops (|((x ) ̅– μ) 100/μ| <RSD tα/√n), supporting its suitability for routine quality control and pharmaceutical analysis.

Abstract licence: CC BY 4.0

Drug-facilitated sexual assault (DFSA) may involve a diverse array of substances, including illicit drugs, prescription medications, and over-the-counter pharmaceuticals. Hair analysis has emerged as a valuable forensic tool, offering an extended window of detection spanning several months. However, interpreting drug concentrations in hair can be challenging in forensic cases, as there are still substantial disparities in drug concentration findings across studies, or even no data available in the literature. This compendium seeks to contribute to the understanding and interpretation of forensic cases involving hair analysis. This study included hair analysis results upon prosecutor request over 6 years in Grenoble Forensic Laboratory from 2019 to 2024. Segmental hair analysis was performed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on Sciex® 5500QT and Waters® TQ-XS mass spectrometers, following Society of Hair Testing guidelines. Screened substances included drugs of abuse, benzodiazepines, sedative medications, and gamma-hydroxybutyrate (GHB), depending on the case, following French Society of Analytical Toxicology guidelines. Hair proficiency quality testing ensured reproducible results. In this compendium, 22 authentic DFSA cases are described with hair analysis. The cohort predominantly involved female victims (95%) aged 13-47 years. Hair analysis was positive in nine cases (41%), revealing the presence of at least one psychoactive substance. Substances identified were alimemazine, alprazolam, bromazepam, cetirizine, clozapine, codeine, cyamemazine, hydroxyzine, oxazepam, zolpidem, and 3,4-methylenedioxymethamphetamine (MDMA). The chemical profile observed primarily included sedating and amnesic pharmaceuticals, but not only. This compendium adds valuable data in the literature for better hair drug concentration interpretation in forensic cases.

Abstract licence: CC BY

This study mainly used The Cancer Genome Atlas (TCGA) RNA sequencing dataset to screen prognostic snoRNAs of acute myeloid leukemia (AML), and used for the construction of prognostic snoRNAs signature for AML. A total of 130 AML patients with RNA sequencing dataset were used for prognostic snoRNAs screenning. SnoRNAs co-expressed genes and differentially expressed genes (DEGs) were used for functional annotation, as well as gene set enrichment analysis (GSEA). Connectivity Map (CMap) also used for potential targeted drugs screening. Through genome-wide screening, we identified 30 snoRNAs that were significantly associated with the prognosis of AML. Then we used the step function to screen a prognostic signature composed of 14 snoRNAs (SNORD72, SNORD38, U3, SNORA73B, SNORD79, SNORA73, SNORD12B, SNORA74, SNORD116-12, SNORA65, SNORA14, snoU13, SNORA75, SNORA31), which can significantly divide AML patients into high- and low-risk groups. Through GSEA, snoRNAs co-expressed genes and DEGs functional enrichment analysis, we screened a large number of potential functional mechanisms of this prognostic signature in AML, such as phosphatidylinositol 3-kinase-Akt, Wnt, epithelial to mesenchymal transition, T cell receptors, NF-kappa B, mTOR and other classic cancer-related signaling pathways. In the subsequent targeted drug screening using CMap, we also identified six drugs that can be used for AML targeted therapy, they were alimemazine, MG-262, fluoxetine, quipazine, naltrexone and oxybenzone. In conclusion, our current study was constructed an AML prognostic signature based on the 14 prognostic snoRNAs, which may serve as a novel prognostic biomarker for AML.

Abstract licence: CC BY-NC-SA

BackgroundM2 macrophages have been reported to be important in the progression of coronary artery disease (CAD). Thus, the present study aims at exploring the diagnostic value of M2 macrophage-associated genes in CAD.MethodsTranscriptome profile of CAD and control samples were downloaded from Gene Expression Omnibus database. The proportion of immune cells was analyzed using cell type identification by estimating relative subsets of RNA transcripts. Weighted Gene Co-expression Network Analysis (WGCNA) was carried out to screen the relevant module associated with M2 macrophages. Differential CAD and control samples of expressed genes (DEGs) were identified by the limma R package. Functional enrichment analysis by means of the clusterProfiler R package. Least absolute shrinkage and selection operator (LASSO) and random forest (RF) algorithms were carried out to select signature genes. Receiver operating curves (ROC) were plotted to evaluate the diagnostic value of selected signature genes. The expressions of potential diagnostic markers were validated by RT-qPCR. The ceRNA network of diagnostic biomarkers was constructed via miRwalk and Starbase database. CMap database was used to screen candidate drugs in the treatment of CAD by targeting diagnostic biomarkers.ResultsA total of 166 M2 macrophage-associated genes were identified by WGCNA. By intersecting those genes with 879 DEGs, 53 M2 macrophage-associated DEGs were obtained in the present study. By LASSO, RF, and ROC analyses, C1orf105, CCL22, CRYGB, FRK, GAP43, REG1P, CALB1, and PTPN21 were identified as potential diagnostic biomarkers. RT-qPCR showed the consistent expression patterns of diagnostic biomarkers between GEO dataset and clinical samples. Perhexiline, alimemazine and mecamylamine were found to be potential drugs in the treatment of CAD.ConclusionWe identified eight M2 macrophage-associated diagnostic biomarkers and candidate drugs for the CAD treatment.

Abstract licence: CC BY