Search Results (93)

Background: Alcohol use disorder is a common condition with high morbidity and mortality and no highly effective treatments. Achieving and maintaining abstinence is necessary or desired for many persons with AUD, but is difficult due to the nature of the condition. Pharmacologic inhibition of the enzyme ALDH2, which increases levels of the substrate acetaldehyde when alcohol is imbibed, can serve as a powerful enforcer of efforts to remain abstinent. Disulfiram is an approved ALDH2 inhibitor via its active metabolite DETC-MeSO, but has many limitations, including numerous adverse effects, hepatotoxicity, oral administration, and unpredictable mechanistic activity. Methods: SOPH-110S, an analog of DETC-MeSO, was evaluated in a series of experiments to assess mechanism, pharmacokinetics in male beagle dogs, cardiovascular safety in telemeterized male beagle dogs, selectivity, off-target activity, CYP inhibition, and proof of mechanism in a rat model that included dosing and alcohol challenge followed by analysis of liver ALDH2 inhibition. Results: SOPH-110S showed high potency with a comparable IC₅₀ vs. positive controls and no physiologically relevant off-target binding in an 84-target panel. It did not inhibit or induce any major CYP enzymes or meaningfully inhibit the hERG channel. After 10 days’ dosing in rats, followed by administration of alcohol, SOPH-110S was a highly potent, dose-dependent inhibitor of ALDH2, comparable to DETC-MeSO. No cardiovascular safety concerns were found at multiples above expected clinical doses. Conclusions: The preclinical data support further clinical study of SOPH-110S as a potential ALDH2 inhibitor treatment for AUD. The FDA approved the IND to conduct a first-in-man phase 1 study in September 2025. Full article

Gelasia tomentosa (L.) Zaika, Sukhor. & N.Kilian which is known formerly as Scorzonera tomentosa L., a wild edible plant species in Turkey, is traditionally used against rheumatism and for wound healing. In this study, we explore its anti-inflammatory compounds, evaluating effectiveness through human red blood cell stabilization and in silico models, alongside physico-chemical and pharmacokinetic profiles. In vitro activity-guided fractionation allowed the isolation of sixteen compounds from the aerial parts of G. tomentosa, which were identified as hyperoside (1), isoquercetin (2), quercetin 3-O-β-apiofuranosyl-(1→2)-β-galactopyranoside (3), quercetin 3-O-β-apiofuranosyl-(1→2)-β-glucopyranoside (4), 7-methoxyapigenin-6-C-β-apiofuranosyl-(1→2)-β-glucopyranoside (5), apigenin-6-C-β-apiofuranosyl-(1→2)-β-glucopyranoside (6), dihydrodehydrodiconiferyl-alcohol-4-O-β-glucopyranoside (7), cichoriin (8), 7-O-methylisoorientin (9), isoorientin (10), swertisin (11), 3,5-O-dicaffeoylquinic acid methyl ester (12), 4,5-O-dicaffeoylquinic acid methyl ester (13), staphylinioside E (14), 3,5-O-dicaffeoylquinic acid (15), and 4,5-O-dicaffeoylquinic acid (16). Compound 16 displayed the highest potential anti-inflammatory activity (IC₅₀ = 0.55 ± 0.00 mg/mL). However, the fraction with compounds displayed stronger biological activity than the isolated ones. In silico findings supported the anti-inflammatory potential, enhancing TP53 expression and cell membrane protection. Cichoriin (8) and staphylinioside E (14) are in accordance with Lipinski’s, Pfizer’s, GSK’s, and Golden Triangle rules, indicating a favorable ADME profile as a drug candidate. Further studies are needed to test this potential in specific inflammation models. Full article

Carotol, the major sesquiterpene alcohol in carrot essential oil, possesses notable cytotoxic activity against various cancer cell lines, yet its metabolic fate remains poorly understood. This study explored microbial biotransformation as a tool for generating novel carotol derivatives with potential pharmacological value. Seventeen microbial strains were screened, with Absidia coerulea ATCC 6647 identified as the most effective biocatalyst. Preparative-scale fermentation with this strain afforded three new metabolites, CM1, CM2, and CM3, in yields of 30%, 9.96%, and 3.28%, respectively, which were structurally characterized by 1D and 2D NMR, HRMS, and single-crystal X-ray diffraction. These were identified as 9α-hydroxydaucol (CM1), 9α,13-dihydroxydaucol (CM2), and a diol derivative of daucol (CM3). Cytotoxicity evaluation against human carcinoma cell lines (HepG-2, HCT-116, MCF-7, A-549) and normal lung fibroblasts (MRC-5) revealed that carotol exhibited notable activity with IC₅₀ values of 25.68 and 28.65 µM against HCT-116 and A-549 cell lines, respectively. Among the metabolites, CM2 showed selective cytotoxicity with IC₅₀ values of 180.64 (HCT-116) and 138.21 µM (A-549), indicating that microbial transformation modulates the cytotoxic profile of carotol and yields metabolites with distinct bioactivity patterns. Molecular docking studies further revealed that carotol and CM2 demonstrated higher binding affinities and more stable interactions with human NADPH oxidase, suggesting that inhibition of this enzyme may underlie their cytotoxic effects. This work provides the first detailed microbial biotransformation pathway of carotol, highlighting A. coerulea as a promising source of new hydroxylated metabolites. The results underscore the potential of carotol derivatives in anticancer drug development and warrant further pharmacokinetic studies. Full article

Gastrodiae Rhizoma (GR) is known to have a medicinal and food-based homology. It is used to treat infantile convulsion, epilepsy, spasm, tetanus, and vertigo. In this study, an ultra-high performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated to quantify fourteen components (p-hydroxybenzyl alcohol, gastrodin, parishin E, p-hydroxybenzoic acid, parishin C, parishin A, parishin B, nicotinamide, p-hydroxybenzaldehyde, adenosine, 3,4-dihydroxybenzaldehyde, syringaldehyde, dauricine, and nobiletin) of GR in rat plasma. Methanol precipitation was used to prepare the samples with astragalin, serving as the internal standard. In multiple reaction monitoring (MRM) mode, the fourteen components were separated by gradient elution on a Waters ACQUITY UPLC^® HSS T3 column. Under these conditions, all fourteen analytes’ calibration curves demonstrated strong linearity within wide concentration ranges (r > 0.9941). Accuracy for the intra-day and inter-day assessments ranged from −13.74% to 12.76%, and the precision for all analytes remained below 8.88%. The analytes’ extraction recoveries ranged from 66.78% to 114.2%, accompanied by matrix effects ranging from 63.65% to 117.61%. Under the evaluated conditions, stability tests confirmed that the compounds remained stable, with relative standard deviations below 13.83%. Consequently, the UHPLC-MS/MS method was effectively used to determine the pharmacokinetics of fourteen components in rat plasma after oral administration of GR extract. This study provides supportive data for rational application of GR. Full article

Anecdotal reports have recently circulated suggesting that intramuscular injection of bacteriostatic saline (BS)—which contains benzyl alcohol (BnOH)—can reverse botulinum toxin type A (BoNTA)-induced brow ptosis. Given the well-established intracellular persistence of BoNTA’s light chain and its irreversible cleavage of SNAP-25, such rapid functional recovery challenges existing pharmacological understanding. This study employed high-resolution pharmacokinetic/pharmacodynamic (PK/PD) modelling using the AesthetiSim™ platform to systematically evaluate this hypothesis. A total of 30,000 virtual patients were randomized to receive BoNTA alone, BoNTA followed by BS injection, or BoNTA followed by normal saline (NS) at Day 7. The model incorporated BoNTA diffusion, internalization, SNAP-25 cleavage, neuromuscular output, and transient BS effects on membrane permeability and endosomal trafficking. Simulated recovery trajectories were tracked over 90 days. The primary outcome, time to 80% restoration of baseline frontalis muscle force (T₈₀), averaged 42.0 days in the BoNTA-only group and 35.5 days in the BS group (Δ = −6.5 days; p < 0.001). Only 13.9% of BS-treated patients reached the T₈₀ threshold by Day 30. Partial reactivation (T₃₀) occurred earlier with BS (21.8 ± 5.3 days vs. 27.3 ± 4.9 days), and the area under the effect curve (AUEC) was increased by 9.7%, reflecting higher overall muscle function over time. In molecular simulations, BnOH produced a minor rightward shift in the BoNTA–SNAP-25 dissociation curve, but receptor occupancy remained above 90% at therapeutic toxin concentrations, suggesting no meaningful impairment of binding affinity. A global Sobol sensitivity analysis demonstrated that the primary driver of recovery kinetics was intracellular LC degradation (49% of T₈₀ variance), while BS-modulated extracellular parameters collectively contributed less than 20%. These findings indicate that BS does not reverse the molecular action of BoNTA but may transiently influence recovery kinetics via non-receptor-mediated pathways such as increased membrane permeability or altered vesicular trafficking. The magnitude and variability of this effect do not support the notion of a true pharmacologic reversal. Instead, these results emphasize the need for mechanistic scrutiny when evaluating rapid-reversal claims, particularly those propagated through anecdotal or social media channels without supporting biological plausibility. Full article

Background/Objectives: Non-Hodgkin lymphoma (NHL) is a group of blood cancers that arise in the lymphatic nodes and other tissues after an injury to the DNA of B/T lineage and NK lymphocytes. Recently, we reported that incomptine A (IA) has in vivo antilymphoma properties. This research aimed to evaluate the effects of IA in the treatment of NHL using antilymphoma activity, Tandem Mass Tag (TMT), and bioinformatics approaches. Methods: The antilymphoma activity of IA was tested on male Balb/c mice inoculated with U-937 cells. Also, TMT, gene ontology enrichment, Reactome pathway, Kyoto Encyclopedia of Gene and Genomes pathway, molecular docking, toxicoinformatic, and pharmaceutical analyses were performed. Results: By TMT analysis of the altered levels of proteins present in the lymph nodes of Balb/c mice with NHL and treated with IA, we identified 106 significantly differentially expressed proteins (DEPs), including Il1rap, Ifi44, Timd4, Apoa4, and Fabp3 as well as Myh3, Eno 2, and H4c11. Among these, the Fhl1 result was the most important cluster altered and a potential core target of IA for the treatment of NHL. Network pharmacology studies have revealed that DEPs are associated with processes such as muscle contraction, glycolysis, hemostasis, epigenetic regulation of gene expression, transport of small molecules, neutrophil extracellular trap formation, adrenergic signaling in cardiomyocytes, systemic lupus erythematosus, alcoholism, and platelet activation, signaling, and aggregation. Computational studies revealed strong binding affinities with six proteins associated with cancer, positive pharmacokinetic properties, and no toxicity. Conclusions: Our contribution suggests that IA may be a compound with potential therapeutic effects against NHL. Full article

Background: Worldwide, the number of cases of parasitic diseases has been increasing; however, available treatments have variable adverse effects and low efficacy, mainly in Neglected Tropical Diseases such as Chagas disease and Leishmaniasis. Therefore, the development of new and more effective antiparasitic drugs is important. Natural products are the source of secondary metabolites with different biological activities, such as antibacterial, anticancer, anti-inflammatory, and antiparasitic. Objectives: In this work, secondary metabolites (phenols and terpenes) from natural products were selected to be evaluated against the epimastigotes of NINOA and A1 strains of Trypanosoma cruzi and the promastigotes of M379 strain and FCQEPS native isolate of Leishmania mexicana. Additionally, their cytotoxicity and selectivity index were determined. Methods: Eighteen secondary metabolites were evaluated in vitro against T. cruzi epimastigotes and L. mexicana promastigotes; additionally, their cytotoxicity on the J774.2 macrophage cell line was determined. Results: The compounds l-(-)-menthol (14, IC₅₀ = 24.52 µM) and β-citronellol (11, IC₅₀ = 21.54 µM) had higher trypanocidal activity than the reference drug (benznidazole) against NINOA and A1 strains of T. cruzi, respectively. On the other hand, para-anisyl alcohol (4, IC₅₀ = 34.89 µM) had higher leishmanicidal activity than the reference drug (glucantime^®) against M379 and the FCQEPS native isolate of L. mexicana. Finally, in silico, the determination of their pharmacokinetic and toxicological properties showed that they are promising candidates for oral and topical uses. Conclusions: This study opens the possibility of using secondary metabolites as scaffolds for access to the development of new molecules for the treatment of parasite diseases. Full article

This study aimed to analyze whether the enhancement of the biopharmaceutical efficiency of mebendazole, a poorly water-soluble anthelmintic drug, significantly improves its antiparasitic activity in a murine model of trichinellosis. Objectives: Two advanced oral formulations were developed, polyvinyl alcohol-derived nanoparticles (NP) and β-cyclodextrin citrate inclusion complexes (Comp), both employing mebendazole as an anthelmintic agent. The primary objective of this work is to treat trichinellosis, an infection with severe chronic effects. Methods: The physicochemical characteristics as well as the in vivo performance of the NP and Comp formulations were assessed. The in vivo studies involved the bioavailability analysis, comparing drug absorption between the pure drug and the novel formulations, as well as the in vitro anthelmintic activity and in vivo therapeutic efficacy against Trichinella spiralis encysted muscle larvae. The in vivo efficacy was evaluated during the parenteral stage of T. spiralis infection in male and female mice from two genetically distinct lines differing in mebendazole pharmacokinetic parameters and susceptibility to the parasite. Results: The formulations exhibited smaller particle sizes and improved dissolution properties compared to pure MBZ. The pharmacokinetics studies indicate that NP and Comp significantly improved MBZ bioavailability. Both NP and Comp significantly increased mebendazole’s anthelmintic activity against the encysted parasites, which would be attributed to the improved MBZ absorption. The formulations overcome the drug’s poor solubility and low bioavailability limitations, resulting in a higher plasma concentration of the active drug, even at low doses. Conclusions: These findings suggest that the newly designed mebendazole formulations are suitable for treating T. spiralis chronic infection and highlight a potential improvement in the pharmacological treatment of trichinellosis. Full article

Background/Objectives: Levocetirizine (LCZ) is a second-generation antihistamine with minimal central nervous system effects. However, its short half-life necessitates daily dosing, potentially reducing adherence in pediatric populations. This study aimed to develop a long-acting injectable LCZ formulation by synthesizing lipophilic prodrugs and evaluating their physicochemical stability, enzymatic hydrolysis, and pharmacokinetics in vivo. Methods: Two prodrugs of LCZ, LCZ decanoate (LCZ-D) and LCZ laurate (LCZ-L), were synthesized via esterification with alkyl alcohols. The compounds were characterized using NMR, FT-IR, and DSC. Prodrugs were formulated with an oil-based vehicle (castor oil and benzyl benozate), and their hydrolysis was evaluated using porcine liver esterase (PLE) and rat plasma. Pharmacokinetic profiles were assessed in Sprague Dawley rats after oral or intramuscular administration. Stability was tested at 25 °C, 40 °C, and 60 °C for 6 weeks. Results: LCZ-D and LCZ-L exhibited first-order hydrolysis kinetics, with rates following the order of PLE (2.0 > 0.5 units/mL) > plasma > PLE (0.2 units/mL). The C_max of LCZ-D and LCZ-L were 13.95 and 5.12 ng/mL, respectively, with corresponding AUC_0–45d values of 6423.12 and 2109.22 h·ng/mL. Formulations containing excipients with lower log P values led to increased systemic exposure. All formulations maintained therapeutic plasma concentrations for over 30 days. The inclusion of the antioxidant BHT (0.03% v/v) improved oxidative stability, reducing degradation at 60 °C from 4.72% to 1.17%. Conclusions: All formulations demonstrated potential for the long-acting delivery of LCZ, maintaining therapeutic plasma levels for over 30 days. Moreover, the release behavior and systemic exposure could be effectively modulated by excipient selection. Full article

Disulfiram (DSF), a well-known anti-alcoholism drug, exhibits potent anticancer activity via its metabolite, diethyldithiocarbamate (DDC), which forms a cytotoxic copper complex that selectively targets cancer stem cells. However, its clinical utility is limited by poor solubility and rapid plasma metabolism. This study explores saccharide-linked DDCs as novel prodrugs designed to enhance stability, solubility, and tumour-selective activation. These compounds feature thioglycosidic bonds that shield the DDC moiety from premature degradation while retaining its metal-chelating function to form the active copper(II)bis(N,N-diethyldithiocarbamate) (Cu(DDC)₂) complex. The synthesised derivatives were characterised and evaluated for serum stability and in vitro cytotoxicity across several cancer cell lines, including colorectal, breast, lung, and brain cancers. Copper-complexed saccharide-DDC prodrugs demonstrated remarkable cytotoxicity, with improved biostability and solubility profiles. These findings highlight the potential of saccharide-linked DDCs as stable, copper-activated prodrugs for cancer therapy. Further in vivo studies are warranted to validate their pharmacokinetics and clinical relevance. Full article

Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut–liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome–mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies—ranging from NAD⁺ repletion and probiotics to fecal microbiota transplantation—that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease. Full article

Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction models involving alcohol, nicotine, psychostimulants, and opioids. In animal studies, glucagon-like peptide-1 receptor agonists consistently reduce drug intake, attenuate dopamine release in reward circuits, and decrease relapse-like behavior. Clinical and observational studies provide preliminary support for these findings, particularly among individuals with comorbid obesity or insulin resistance. However, several translational barriers remain, including limited blood–brain barrier penetration, species differences in pharmacokinetics, and variability in treatment response due to genetic and metabolic factors. Ethical considerations and methodological heterogeneity further complicate clinical translation. Future directions include the development of central nervous system penetrant analogues, personalized medicine approaches incorporating pharmacogenomics, and rigorously designed trials in diverse populations. Glucagon-like peptide-1 receptor agonists may offer a novel therapeutic strategy that addresses both metabolic and neuropsychiatric dimensions of addiction, warranting further investigation to define their role in the evolving landscape of substance use disorder treatment. Full article

Background/Objectives: This study investigates the phytochemical composition and anticancer activity of Melaleuca quinquenervia leaf essential oil (MQLEO) from Egypt. Methods: Chemical profiling was performed using GC/MS. Anticancer activity was assessed through cytotoxicity screening against multiple cancer cell lines, with a subsequent evaluation of cell migration, apoptosis, and cell cycle analysis on the most sensitive line (A549). Network pharmacology and molecular docking analyses were employed to identify potential molecular targets and pathways. Results: GC/MS analysis revealed a unique profile dominated by 1,8-cineole (31.57%), α-pinene isomers (both 1R and 1S forms, collectively 21.26%), and sesquiterpene alcohols (viridiflorol: 13.65%; ledol: 4.55%). These results diverge from prior studies, showing a 25.63% decrease in 1,8-cineole and no detectable α-terpineol, suggesting environmental, genetic, or methodological impacts on biosynthesis. In vitro tests revealed selective cytotoxicity against A549 lung cancer cells (IC₅₀ = 18.09 μg/mL; selectivity index = 4.30), meeting NCI criteria. Staurosporine was used as a positive control to validate the assays, confirming the reliability of the methods. MQLEO also inhibited cell migration (62–68% wound closure reduction) and induced apoptosis (24.32% vs. 0.7% in controls). Cell cycle arrest at the G₀-G₁ phase implicated cyclin-dependent kinase regulation. Network pharmacology identified ESR1, CASP3, PPARG, and PTGS2 as key targets, with MQLEO components engaging apoptosis, inflammation (TNF, IL-17), and estrogen pathways. Conclusions: MQLEO demonstrates promising anticancer activity through multiple mechanisms including apoptosis induction, cell cycle arrest, and migration inhibition. The multi-target activity profile highlights its potential as a therapeutic candidate for lung cancer, warranting further in vivo validation and pharmacokinetic studies to advance clinical translation. Full article

Background/Objectives: Cancer remains one of the leading causes of mortality globally, underscoring the need for novel therapeutic strategies capable of targeting multiple molecular pathways simultaneously. Natural products, particularly fungal-derived metabolites from the genus Cordyceps, represent promising candidates due to their diverse biological activities. Although previous studies have indicated the anticancer potential of Cordyceps species, systematic characterization of their molecular targets has been limited. This study aimed to comprehensively identify and evaluate Cordyceps metabolites as potential multitarget anticancer agents through a network pharmacology approach. Methods: A total of 129 metabolites previously reported in the literature from polar aqueous, alcoholic, and non-polar extracts of Cordyceps were compiled and chemically classified using ChemMine tools. Structure-based target prediction and pathway enrichment analyses were performed to investigate their potential biological targets. Predicted molecular targets were cross-referenced with differentially expressed genes in breast, colorectal, and lung cancers to identify hub proteins. Molecular docking simulations were conducted to assess binding affinities of metabolites to key oncogenic targets, and SwissADME was utilized for pharmacokinetic profiling. Results: The analysis revealed that Cordyceps metabolites targeted critical oncogenic pathways, including cell cycle regulation, DNA replication, and apoptosis. Hub proteins such as TYMS, AURKA, and CDK1 were identified as primary targets. Docking simulations highlighted metabolites such as cordycepsidone A, jiangxienone, and flazin, demonstrating binding affinities comparable or superior to clinically used inhibitors. Pharmacokinetic profiling identified several metabolites with favorable drug-like properties, supporting their potential as lead compounds. Conclusions:Cordyceps extracts contain structurally diverse metabolites capable of modulating multiple cancer-relevant molecular targets, providing a robust foundation for their development into multitarget anticancer therapies. This integrative network pharmacology approach underscores the potential of fungal metabolites in oncology drug discovery. Full article

Background: Despite the well-established liver-protective efficacy of monoammonium glycyrrhizinate (MONO), diammonium glycyrrhizinate (DIAM), and magnesium isoglycyrrhizinate (MAGN), which has been translated into clinical practice, their clinical differentiation remains elusive owing to their structural similarities and overlapping therapeutic effects. Methods: The present study delves into the pharmacokinetics, cellular-level liver-protective potencies, and underlying mechanisms of action of these three compounds through a comprehensive analysis. Results: The findings reveal that both DIAM and MAGN exhibit superior bioavailability and hepatoprotective profiles compared to MONO. Notably, an investigation of the metabolic pathways mediating liver protection in normal human liver cells (LO2), utilizing an ultra-performance liquid chromatography–time of flight tandem mass spectrometry (UPLC-TOF-MS/MSe) platform, demonstrated that MAGN augments antioxidant components, thereby favoring its application in drug-induced liver injury (DILI). Conversely, DIAM appears to be a more suitable candidate for addressing non-alcoholic fatty liver disease (NAFLD) and viral hepatitis. Conclusion: This study contributes novel perspectives on the mechanisms of action and potential clinical utilities of DIAM and MAGN in liver disease prevention and management. Full article