Fluspirilene 12mg/6ml suspension for injection vials

Antipsychotic-associated metabolic toxicity remains one of the most persistent clinical problems in psychopharmacology. Clozapine and olanzapine are especially effective for psychosis but carry high liability for weight gain, dyslipidemia, insulin resistance, and type 2 diabetes. Current monitoring recommendations recognize this risk, yet they remain largely uniform across patients and do not incorporate ancestry-specific genetic risk or mechanistic drug-gene information. We performed a transcriptome-wide association study-informed drug-gene prioritization analysis to examine whether approved antipsychotic target genes overlap with genes whose genetically predicted expression is associated with type 2 diabetes. The analysis used ancestry-specific type 2 diabetes transcriptome-wide association study (TWAS) results derived from a multi-ancestry genome-wide association study (GWAS) and approved antipsychotic drug-gene interactions from the Drug-Gene Interaction Database (DGIdb). For each drug, target genes were matched to TWAS genes across six metabolic tissues, and a weighted risk score was calculated as the sum of the absolute TWAS z-score multiplied by the drug-gene interaction score for significant targets. Follow-up analyses decomposed signals into targets with positive and negative TWAS directions, operationally interpreted as aggravating and compensatory, while also examining curated metabolic axis genes including GLP1R, GIPR, PPARG, and SLC2A4. The analysis identified recurrent exploratory target-overlap signals for clozapine and olanzapine. Clozapine showed the most consistent cross-ancestry aggravating profile, with recurrent target overlap involving GLP1R and immune-related genes. Olanzapine showed strong mechanistic-axis overlap involving GLP1R, GIPR, and PPARG, although its simple TWAS directionality was often classified as compensatory. Trifluoperazine emerged as a notable candidate, with significant target enrichment in the European ancestry analysis and top ranking in the Hispanic analysis. Fluspirilene also met the combined enrichment false discovery rate threshold in the European ancestry analysis, although its clinical metabolic interpretation was less direct. Haloperidol decanoate showed a high burden driven partly by SLC2A4, but its directionality was frequently mixed or compensatory. These findings nominate the incretin axis as a plausible translational bridge between antipsychotic metabolic liability and existing interventions such as GLP-1 receptor agonists. They also identify a key methodological gap. Future models must incorporate the pharmacologic mode of action to distinguish receptor blockade from activation. Except for the enrichment-positive European ancestry findings for trifluoperazine and fluspirilene, the results are exploratory prioritization signals and do not establish drug-specific metabolic effects, causal mechanisms, or ancestry-specific treatment effects. Overall, this TWAS-informed analysis provides a hypothesis-generating framework for ancestry-aware metabolic monitoring and targeted validation studies.

Abstract licence: CC BY

Trichinella spiralis is a parasitic nematode that causes trichinellosis, leading to weakness, muscle pain, facial edema, and potentially death. Albendazole (ABZ) is the current drug of choice; however, resistance has been increasingly reported, highlighting the urgent need for novel therapeutics. Developing new drugs is costly and time-consuming, making computational approaches and drug repurposing attractive alternatives. In this study, we combined metabolomics and virtual screening to identify potential anthelmintic candidates for trichinellosis and ABZ-resistant nematodes. Both adult and larval T. spiralis were treated with ABZ, then untargeted metabolomics were performed. Over 11,000 features were detected using the XCMS platform, with 122 and 133 metabolites significantly altered in adults and larvae, respectively. Pathway analysis with MetaboAnalyst identified fatty acid degradation as a key pathway affected by ABZ. Since this pathway is essential for worm lipid metabolism, we targeted the enzymes carnitine palmitoyltransferase (CPT) 1 and 2, which transport fatty acids into mitochondria. Virtual screening against parasite and human CPTs identified 87 compounds that selectively bind the parasite proteins. Lumacaftor, entrectinib, and fluspirilene showed the lowest binding energies and were tested in vitro. In larval T. spiralis, fluspirilene and entrectinib killed the parasites at concentrations of 266.8 and 442.6 μg/ml, respectively, while lumacaftor showed no activity. Importantly, entrectinib also killed both ABZ-sensitive and ABZ-resistant Caenorhabditis elegans at lower concentrations than ABZ, demonstrating potent activity against resistant nematodes. Our findings suggest that entrectinib is a promising candidate for a novel anthelmintic, with potential to overcome ABZ resistance in trichinellosis and other parasitic infections.

Abstract licence: CC BY-NC-ND

AimIn hepatocellular carcinoma (HCC), molecularly targeted therapies have been the major focus of recent research. In this study, we evaluated the clinical and biological roles of tumor necrosis factor superfamily 4 (TNFSF4), an inflammatory cytokine, as a therapeutic target in HCC.MethodsUsing a bioinformatics approach, we identified TNFSF4 as a candidate driver in HCC and assessed the prognostic significance of TNFSF4. Its biological role in HCC was clarified through in vitro experiments, such as cell cycle/colony formation assays, using TNFSF4-overexpressing HCC cells. Moreover, a candidate repositioned drug was identified from public drug sensitivity data, and its antitumor effects and mechanisms were examined both in vitro and in vivo.ResultsAnalysis of The Cancer Genome Atlas datasets for HCC revealed that TNFSF4 was overexpressed in HCC cells owing to increased DNA copy numbers. Additionally, high TNFSF4 expression was significantly associated with poorer prognosis. Immunohistochemical staining showed that TNFSF4 was overexpressed in the cytoplasm of tumor cells. In vitro analysis showed that TNFSF4 overexpression promoted the G1/S transition in the cell cycle, stimulated proliferation, and increased phosphoinositol-3-kinase (PI3K) phosphorylation, resulting in p21 downregulation and enhanced Rb phosphorylation. In bioinformatics-based drug repositioning analysis, fluspirilene, a typical antipsychotic agent, was identified as a repositioned drug that inhibited HCC growth through cyclin D1 suppression, downstream of TNFSF4.ConclusionsTNFSF4 was a candidate driver and a prognostic biomarker, promoting HCC progression by activating the PI3K/Akt signaling pathway. Furthermore, fluspirilene may have applications as a repositioned drug for HCC with high TNFSF4 expression.

Abstract licence: CC BY

Abstract Background: White matter injury (WMI) is a major cause of neurological impairment in preterm infants, characterized by demyelination due to disrupted oligodendrocyte precursor cell (OPC) maturation. Currently, no effective treatment exists. This study investigates the role of paired immunoglobulin-like receptor B (PirB) and the novel programmed cell death pathway—pan-apoptosis (PANoptosis)—in the pathogenesis of WMI. Methods: A neonatal rat model of WMI was established via intracerebroventricular injection of lipopolysaccharide (LPS). PirB expression was modulated using the inhibitor Fluspirilene or siRNA-mediated silencing. The NLRP3 inhibitor MCC950 was employed to assess its role in PANoptosis. Histopathological changes were evaluated by H&E staining and transmission electron microscopy; myelin integrity and cell death were assessed via immunofluorescence and Western blotting. Mitochondrial DNA (mtDNA) release and NLRP3 interaction were visualized using confocal microscopy. Results: PirB was significantly upregulated in OPCs following WMI. Silencing PirB or inhibiting it with Fluspirilene reduced demyelination and white matter damage, decreased inflammation (IL-18 and TNF-α), and attenuated PANoptosis—simultaneously suppressing apoptosis, pyroptosis, and necroptosis. Mechanistically, PirB activation promoted mtDNA release into the cytoplasm via the Bax/Bak pathway, leading to NLRP3 inflammasome assembly and PANoptosome formation. Inhibition of NLRP3 with MCC950 similarly reduced all three forms of OPC death. Conclusions: PirB contributes to WMI by activating NLRP3-mediated PANoptosis in OPCs, leading to impaired myelination. Targeting the PirB/NLRP3 signaling axis may represent a promising therapeutic strategy for mitigating WMI in preterm infants.

Abstract licence: CC BY

BackgroundA drug designed for a specific target often interacts with multiple targets, either unintentionally or as part of its intended mechanism of action. This has been called pharmacological pleiotropy or polypharmacology. There are key endogenous ligands such as ATP, GABA and glutamate that act on various proteins in humans. Furthermore, several drugs act on multiple proteins without apparent structural similarity. G protein-coupled receptors (GPCRs) and protein kinases are among the most important families of drug targets. The aim of this review analysis is to identify drugs with dual actions on GPCRs and kinases and clarify what is known about these actions.ApproachData searches for ligands with affinity for both kinases and GPCRs were conducted in the Drugbank and Pharos databases. Physiochemical properties of selected compounds were identified using the rdMolDescriptors module from RDKit. A detailed literature search was conducted in search engines such as Google Scholar and Medline, to identify pleiotropic compounds with both GPCR and kinase affinity.OutcomeThirty-four compounds were identified to interact with proteins within both the kinase and GPCR protein families. Notable examples included the drugs loratadine, terfenadine, clozapine, thioridazine, aripiprazole, fluspirilene, sorafenib, dasatinib and fasudil.ConclusionsDrug pleiotropy among GPCRs and kinases is a occurring phenomenon. Structural factors that may contribute to pleiotropy include chemical similarity to endogenous ligands, lipophilicity and planarity of chemical structure, which may guide the development of drugs with intentional multi-target effects. Although pleiotropy presents challenges in ensuring selectivity, it also creates opportunities for innovative therapeutic strategies if strategically applied.

Abstract licence: CC BY