Background/Objectives: Hepatocellular carcinoma (HCC) is the most prevalent primary liver tumor and is often diagnosed at advanced stages with very poor therapeutic response, leading to high mortality. Thus, new therapeutic strategies and biomarkers are urgently needed. We previously showed that the combination of loratadine, raloxifene, and sorafenib exerts synergistic cytotoxicity on HCC cells. Here, we explored potential molecular mechanisms underlying the anticancer effects of this combination using multiomics analyses. Methods: We performed proteomic analyses based on mass spectrometry, transcriptomic analyses using the Clariom D Plus human microarray (Affymetrix), and metabolomic analyses based on nuclear magnetic resonance to investigate the profile changes induced by the drug combination in HuH7 cells. Bioinformatic analyses were applied to associate the omics changes with biological functions, molecular interactions, and clinical relevance in terms of patient survival. Results: We identified several molecules whose expression changed in response to treatment across the three omics profiles analyzed. Some of them were found to be involved in hallmarks of cancer, including sustained proliferation, evasion of growth suppressors, and resistance to cell death. Integrated multi-omics analyses revealed that the drug combination suppresses critical oncogenic drivers (C7orf50, NUP188, and HS2ST1) and that the mitotic cell cycle process, DNA synthesis and cholesterol biosynthesis are the primary pathways affected. Protein-protein interaction analysis revealed five key hubs (KIF2C, PCNA, TRIP13, NDC80, and RPA3), whose expression in HCC is associated with poor clinical prognosis. Conclusions: The combined treatment rewired molecular networks involved in HCC progression. These findings identify clinically relevant molecular targets associated with poor prognosis and provide mechanistic insights into the synergistic anticancer activity of this drug combination.

Sensitive and selective green UV-spectrophotometric univariate and multivariate chemometric methods were developed to resolve the overlapped spectra of rupatadine fumarate (RUP), its impurity desloratadine (DES), and methyl paraben (MP). The univariate approach employed was the dual-wavelength (DW) method. Guided by artificial intelligence (AI) in the selection of the optimal wavelength pair, the determination of RUP was performed at 230 and 284.3 nm, and for MP at 236.6 and 253.8 nm. Among the multivariate methods, ANN demonstrated superior predictive accuracy (lowest RMSEP values), followed by PLS-1 and MCR-ALS, highlighting the power of machine learning for complex mixture resolution, particularly in the presence of the preservative MP. A three-factor, five-level experimental design was adopted to construct a calibration set comprising 25 mixtures with varying component ratios, along with 6 independent validation mixtures. The developed methods were successfully applied to pharmaceutical formulation containing the studied drug and were validated in accordance with International Conference of Harmonization (ICH) guidelines. The results obtained were reliable and reproducible, confirming the suitability of these methods for routine analysis and quality control in laboratories. Moreover, the GLANCE tool (Graphical Layout for Analytical Chemistry Evaluation) offered a clear visual summary of the twelve structured method attributes.

Benjakul (BJK) remedy, traditionally used to balance the four elements, has demonstrated clinical efficacy in relieving inflammation and allergic rhinitis (AR) symptoms. This study investigated differential serum peptide expression in AR patients treated with BJK remedy compared to loratadine using MALDI-TOF MS and LC-MS/MS. MALDI-TOF MS revealed four shared mass peptide patterns that were significantly upregulated (p < 0.05) after 3 and 6 weeks of both treatments. Identifying the peptides, 17β-hydroxysteroid dehydrogenase (17β-HSD) and microtubule-actin cross-linking factor 1 (MACF1) were linked to inflammatory suppression and hormonal balance, while zinc finger CCCH-type containing 4 (ZC3H4) and transducin beta-like protein 3 (TBL3) were associated with the relief of pulmonary fibrosis. Conversely, zinc finger homeobox 3 (ZFHX3) and transformation/transcription domain-associated protein (TRRAP) remained elevated after treatment, potentially promoting persistent inflammation via E2F transcription factor 1- (E2F1-) and E2F transcription factor 4- (E2F4-) mediated transcription. Among 1113 peptides identified by LC-MS/MS (selected using a significance threshold of p < 0.05, without a fixed fold-change cutoff), 6-week treatment with BJK remedy significantly downregulated UBQLN1 (4.562-fold; p = 0.016), suppressing toll-like receptor (TLR) activation and B-cell proliferation. It also upregulated Prostaglandin E synthase 2 (PTGES2) and PDZ and LIM domain protein 2 (PDLIM2) (7.841-fold and 8.697-fold, respectively; p = 0.004 and 0.002), while enhancing antioxidant and immunoregulatory responses via ATP-binding cassette subfamily B member 8 (ABCB8) and ADP-ribosylation factor GTPase-activating protein 3 (ARFGAP3). By comparison, 3 weeks loratadine treatment significantly downregulated E2F transcription factor 3 (E2F3) and general transcription factor IIIC subunit 6 (GTF3C6) (p = 0.034 and 0.017) and upregulated CTD small phosphatase like 2 (CTDSPL2), suggesting a distinct but complementary anti-inflammatory mechanism. Together, these findings enhance the understanding of AR pathophysiology and may help to elucidate the mechanisms of BJK remedy and loratadine in treatment, supporting the further development of targeted therapies and biomarkers.

Background/Objectives: Cervical cancer (CC) is the most clinically significant HPV-associated malignancy. Platinum-based chemotherapies produce drug resistance and serious adverse effects. Drug repurposing and combinations are promising approaches to improve the antitumor response. Here, we evaluated the antineoplastic potential of loratadine and simvastatin alone and in combination with cisplatin and gefitinib in HPV-positive CC cells. Methods: HeLa and SiHa CC cells were treated with loratadine, simvastatin, cisplatin, gefitinib, or their combinations. Metabolic activity was assessed using the MTT assay to determine drug inhibitory concentrations (IC20, IC50) from concentration-response curves. Apoptosis was assessed by Annexin V-FITC/PI flow cytometry. Clonogenic survival and migratory capacity were evaluated using colony formation and wound-healing assays, respectively. Tumor formation was evaluated in vivo using the chick chorioallantoic membrane model. Results: Metabolic activity decreased in a concentration-dependent manner following drug treatment in both cell lines. Several combination regimens at IC20 significantly improved reductions in metabolic activity and increases in apoptosis compared with monotherapies or two-drug combinations. Notably, some three-drug combinations, with or without cisplatin, had similar effects to the quadruple regimen. Combination treatments also reduced clonogenic survival and migratory capacity, as well as tumor formation and cancer cell dissemination in vivo. Conclusions: Drug combinations at relatively low concentrations (IC20) significantly enhanced the anticancer effects on CC cells in in vitro and in vivo settings. These findings support the potential of drug repurposing and combination strategies as promising approaches to decrease adverse side effects while improving therapeutic efficacy for the benefit of CC patients.

Loratadine is a common over-the-counter second-generation H1-antihistamine used to relieve and treat seasonal allergy symptoms. While first-generation H1-antihistamines are historically known to cause central nervous system (CNS) side effects, these effects are thought to be far less common in second-generation antihistamines. Similarly, alcohol is known to have CNS effects. We report a case of a 26-year-old female who presented to the emergency department (ED) after a suicide attempt involving loratadine and alcohol ingestion. Emergency medical services (EMS) reported that the patient became unresponsive upon arrival at the ED. An empty loratadine bottle that was supposed to contain 60 tablets was found at the scene. Additionally, an empty bottle of wine was also found at the scene. Initial vital signs and glucose levels were normal, but on examination, the patient had a Glasgow Coma Scale of 3 with rightward eye deviation and developed tonic-clonic seizures, which were quickly controlled with 4 mg of intravenous (IV) lorazepam. She gradually regained responsiveness and received 3200 mg of levetiracetam IV. Toxicological workup revealed a serum ethanol level of 119 mg/dL and a urine toxicology screen positive for benzodiazepines, likely due to lorazepam administration. The patient had mildly elevated lactate and creatine kinase levels consistent with seizure, which normalized after fluid resuscitation. The patient recovered fully without further seizures and was not prescribed antiepileptic medication upon discharge. We present the case to document a potential seizure provoked by the combined ingestion of loratadine and alcohol.

Poor aqueous solubility and complex supersaturation behaviour of small-molecule drugs require rapid, material-sparing analytical tools that capture incipient aggregation and phase separation events under non-equilibrium conditions. This work evaluated a miniaturised optical platform that combined second harmonic scattering (SHS) with linear light scattering (LLS) driven by an ultrafast 1030 nm laser to monitor supersaturated solutions of 12 poorly water-soluble drugs prepared by DMSO solvent shift in 384-well plates. LLS and SHS signals were recorded after 1 h and 24 h and compared with apparent solubilities from a parallel solvent-shift HPLC assay. LLS, which reports on particle size/number, detected precipitation onsets typically close to or below HPLC values and could resolve particle formation down to ∼ 0.1 µM for pimozide, substantially exceeding the sensitivity of standard nephelometric methods. SHS, which is sensitive to interfacial asymmetry and nonlinear susceptibility, often showed onsets and complex peak-drop-rise patterns that deviated from LLS, particularly for lopinavir, loratadine, and ritonavir, indicating structurally distinct, largely centrosymmetric drug-rich assemblies above the solubility limit. Orthogonal characterization by scanning electron microscopy, Capflex (capillary flow with a hydrophobic fluorescent tracer), and confocal fluorescence microscopy provided independent evidence for droplet-like or amorphous drug-rich domains that preceded bulk precipitation. Together, the results showed that combined SHS-LLS enabled highly sensitive detection of precipitation, while revealing multistep, non-classical aggregation pathways in pharmaceutical supersaturated systems.

Toxoplasmosis remains a major global health concern, particularly in immunocompromised individuals and pregnant women, while currently available therapies are associated with significant toxicity and limited efficacy against chronic infection. Drug repurposing represents an attractive strategy for the identification of safer and more effective anti-Toxoplasma gondii agents. This study investigated the antiparasitic potential of loratadine, a second-generation antihistamine, using an integrated in silico, in vitro, and in vivo approach. The anti-T. gondii activity of loratadine was evaluated through β-galactosidase-based proliferation assays, reversibility assays, and experiments using pretreated tachyzoites. In vivo efficacy was assessed in murine models of acute and chronic toxoplasmosis. Disease progression, survival, parasite burden, and cerebral cyst formation were analyzed following treatment. Loratadine inhibited the intracellular proliferation of T. gondii tachyzoites in a concentration-dependent manner and induced partially irreversible effects on parasite viability after drug withdrawal. Pretreatment of extracellular tachyzoites produced limited effects, suggesting that loratadine predominantly acts during the intracellular stage of infection. In the acute toxoplasmosis model, loratadine treatment delayed disease progression, prolonged animal survival, and significantly reduced the number of tachyzoites recovered from the peritoneal cavity. In the chronic infection model, treatment significantly decreased both the number and size of cerebral cysts, although these findings do not demonstrate cyst eradication or direct bradyzoite killing. Despite its measurable biological activity, loratadine exhibited a relatively low in vitro selectivity index, highlighting the need for further optimization. These exploratory findings identify loratadine as a promising lead compound (hit) for further optimization rather than an immediately translatable therapeutic candidate. Additional medicinal chemistry, pharmacokinetic, mechanistic, and confirmatory preclinical studies will be required to determine its potential for anti-T. gondii drug development.

The generation of N-nitrosamine compounds (NOCs) in drugs presents a critical regulatory challenge owing to their potential mutagenicity and exceptionally strict acceptable intake limits required for patient safety. These impurities arise primarily from the reaction between amine-containing active pharmaceutical ingredients and trace amounts of nitrosating agents (reactive NOx), which contribute to N-nitrosation. Reactive NOx species are frequently found in pharmaceutical excipients. Therefore, efficiently reducing reactive NOx is essential for robust management of the risk posed by NOCs. In this study, we employed ultraviolet (UV) irradiation of excipients as a novel preemptive strategy to reduce reactive NOx levels. Desloratadine was used as a secondary amine model to evaluate the generation of N-nitrosamine in physical mixtures with various excipients. The excipients were exposed to different UV wavelengths (248, 313, and 365 nm), and N-nitrosodesloratadine (NDLRT) generation was quantified after storage under stress conditions. We found that 365 nm UV irradiation was the most effective in reducing reactive NOx under all conditions. In a formulation study, 365 nm UV irradiation successfully reduced NDLRT generation in the tablet by 54-68% compared with the control. Overall, the novel strategy described herein should be useful for reducing NOCs without affecting the quality of drugs.

Allergic diseases are common among women of reproductive age, which necessitates the use of antihistamine therapy during pregnancy while ensuring safety for both the mother and the foetus. The study aimed to determine the safety profile, pharmacological characteristics, and clinical consequences of antihistamine use during pregnancy for the maternal-foetal system. A systematic review of scientific publications for the period 2020-2025 was carried out using the PRISMA methodology with a search in five international databases, which allowed us to select 45 relevant sources analyzing pathophysiology, pharmacology, and clinical consequences. It has been established that maternal immunoglobulins of class E are transported across the placental barrier, where they may sensitise foetal mast cells in utero. Hormonal changes during pregnancy induce polarisation of the immune response towards Th2 with progressive suppression of eosinophils by 17-22 % in the second trimester and by 20-42 % in the third trimester. Population cohort studies covering more than 1.2 million pregnancies have found no statistically significant associations between the use of second-generation antihistamines and major congenital malformations, spontaneous abortions or premature births. Physiological changes during pregnancy modify the pharmacokinetic parameters of drugs, reducing plasma protein concentrations by 20-40 %, However, cetirizine and loratadine demonstrate a favourable safety profile based on data from more than 186,000 exposures in Scandinavian registries, and the relative infant dose remains below the 5 % safety threshold. The findings support the use of second-generation antihistamines as first-line therapy for allergic diseases in pregnancy and provide an evidence base for selecting safe pharmacological agents at different gestational stages.

Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), remains a leading cause of mortality from infectious disease worldwide. The continued emergence of multidrug-resistant strains highlights the urgent need for new therapeutic agents with novel mechanisms of action. Here, we report the discovery and comprehensive characterization of DL25, a synthetic desloratadine-derived small molecule exhibiting potent antimycobacterial activity (minimum inhibitory concentration (MIC) 2-4 μg/mL against multiple mycobacterial species). Using a supra-inhibitory DL25 selection strategy, we isolated and characterized spontaneous resistant mutants. Whole-genome sequencing identified recurrent mutations in aroB, which encodes 3-dehydroquinate synthase (DHQS), an essential enzyme of the shikimate pathway. Consistent with target involvement, aroB overexpression reduced susceptibility to DL25, while DL25 decreased DHQS-associated biochemical activity in vitro with an apparent IC50 of approximately 5.0 μg/mL. In addition, DL25 exhibited concentration- and time-dependent bactericidal activity and showed partial synergy with several established antitubercular agents. Structural modeling, molecular docking, and 100 ns molecular dynamics simulations supported stable binding of DL25 within the DHQS active site and identified interactions with residues implicated in substrate recognition and catalysis. Collectively, the genetic, biochemical, and computational findings support DHQS as a biologically relevant target associated with DL25 activity and establish DL25 as a promising lead-like scaffold for the development of future shikimate pathway-directed antimycobacterial agents. More broadly, this study demonstrates the value of integrating genetic, biochemical, and computational approaches for mechanism-guided antituberculosis drug discovery.