Objectives Amantadine (AMD) is an antiviral and antiparkinsonian drug with a narrow therapeutic window and a recognized risk of severe intoxication. Interpretation of postmortem drug concentrations is complicated by postmortem redistribution (PMR), yet systematic toxicokinetic and multi-tissue PMR data for amantadine remain limited. Methods An integrated investigation of amantadine toxicokinetics and postmortem redistribution was conducted in male rats. For toxicokinetic assessment, a single oral dose of 450 mg/kg (LD50) was administered, and concentrations were quantified in blood and nine tissues over a 96-h period. For the PMR study, rats received low (42 mg/kg), medium (LD50), and high (2 × LD50) doses, followed by controlled postmortem storage at 4 °C and 20 °C for up to 96 h. Amantadine concentrations were determined using validated HPLC–MS/MS methods and analyzed by pharmacokinetic and statistical approaches. Results Amantadine was rapidly absorbed and widely distributed, exhibiting pronounced tissue-specific heterogeneity. The liver and kidney showed the highest exposure, whereas accumulation in the brain and testis was limited. Postmortem redistribution was substantial and tissue dependent, and was strongly influenced by dose, postmortem interval, and storage temperature. Blood concentrations were unstable over time, while solid organs, particularly the liver and spleen, exhibited higher and more sustained postmortem concentrations. Notably, selected inter-tissue concentration ratios (e.g., liver-to-lower limb muscle and spleen-to-brain) displayed consistent, dose-dependent trends across postmortem conditions. Conclusions This study provides a comprehensive characterization of amantadine toxicokinetics and postmortem redistribution across multiple biological matrices. The findings underscore the limitations of relying solely on postmortem blood concentrations and support the complementary use of selected tissues and inter-tissue concentration ratios as comparative indicators in toxicological interpretation. These results offer mechanistic insight into postmortem drug dynamics and provide practical reference data to improve the interpretation of suspected amantadine intoxication.

Background/Objectives: This study aimed to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantifying amantadine (AMA) in rat plasma and to investigate its pharmacokinetics under simulated high-altitude hypoxia, contrasting its behavior with that of its structural analog memantine (MEM). Methods: The method entailed using memantine (MEM) as an internal standard. Sample preparation involved protein precipitation, followed by gradient elution with detection via positive electrospray ionization and selective reaction monitoring (SRM). The method validation complied with the International Conference on Harmonization (ICH) M10 guidelines. Pharmacokinetic studies were conducted in rats exposed to either low altitude (1500 m) or simulated high altitude (6500 m) after a single oral dose of AMA (10 mg/kg). Results: The assay demonstrated linearity from 5 to 1000 µg/L, with accuracy, precision, recovery, and stability all meeting the respective acceptance criteria. Hypoxia did not significantly alter systemic exposure to AMA, as measured by parameters such as the area under the concentration-time curve (AUC), maximum concentration (Cmax), and apparent clearance (CLz/F). However, hypoxia prolonged the elimination half-life by 55% and increased the variance in the mean residence time. This finding contrasts sharply with our previous results on MEM under identical hypoxic conditions, which showed a 72.15% increase in AUC and a 41.99% decrease in CLz/F. Conclusions: A robust UPLC-MS/MS method for quantifying AMA was successfully established. AMA exhibits unique pharmacokinetic resilience to acute hypoxia, characterized by increased variability in elimination without changes in overall exposure. This profile starkly differs from the heightened exposure and reduced clearance observed for drugs like MEM, which are predominantly cleared by hepatic metabolism (under the studied conditions). These findings are consistent with the concept that a drug's primary elimination pathway (renal excretion vs. hepatic metabolism) critically determines its pharmacokinetic susceptibility to hypoxic stress.

In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative determination of amantadine in human plasma, with the incorporation of an internal standard to improve analytical accuracy. Plasma samples collected from volunteers were processed using acetonitrile-methanol (3:1, v/v) as the extraction solvent, followed by protein precipitation and purification via the QuEChERS (Quick, Easy, Cheap, Efficacious, Rugged, and Safe) method. Analysis was performed using LC-MS/MS under multiple reaction monitoring mode, with a total run time of 8 min. Quantification was carried out using the internal standard method. After a single oral administration of 200 mg amantadine hydrochloride, plasma concentrations were measured at various time points. Pharmacokinetic parameters were derived by fitting the data to a pharmacokinetic model using specialized software. The results demonstrated good linearity over the range of 0.5–20 ng/mL, with a correlation coefficient (R2) of 0.9978. The extraction recovery ranged from 94.5% to 110.1%, and both intra-day and inter-day relative standard deviations (RSD) were below 10%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.15 ng/mL and 0.5 ng/mL, respectively. The absorption and elimination processes of amantadine in plasma followed first-order kinetics, with R2 > 0.9. Notably, gender-specific differences were observed in the time to maximum concentration (Tmax) and maximum concentration (Cmax): females achieved a Cmax of 670.23 ng/mL at 4 h, whereas males reached a Cmax of 650.87 ng/mL at 8 h. This LC-MS/MS method is simple, rapid, and accurate, rendering it suitable for pharmacokinetic studies of amantadine in humans. Additionally, the established kinetic model provides valuable references for clinical medication guidance.

Relevance. Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed countries after Alzheimer's disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1,900 per 100,000 in people over 80 years of age. Purpose of the study. Based on experimental research into behavioral and cognitive-mnestic disorders of the central nervous system in a Parkinson’s disease (PD) model, the aim was to substantiate the development of potential therapeutic regimens with specific neuroprotective effects on the dopaminergic system. Materials and methods. The study was carried out on 90 Wistar rats, aged of 6 months and weighing 220-290 grams. Parkinsonism was induced by the administration of the neurotoxin MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to experimental rats. The intact group received a single intraperitoneal saline solution of 1 ml per 100 g of body weight, and the control group, after administration of MPTP, received a single intraperitoneal saline solution at the same dosage. The verification for the strategy of rational therapy in Parkinson's disease was based on studying the activity of drugs in groups of animals: group I – Intact (passive control); group II – animals with experimental Parkinson's disease (PD, active control); group III – PD + Amantadine (AM) IV – PD + AM + Cerebrocurin; group V – PD + AM + Pramistar; group VI – PD + AM + Gliatilin; group VII – PD + AM + Noofen; group VIII – PD + AM + Pronoran; group IX – PD + AM + Melatonin. Results. Induction of Parkinson’s disease led to increased anxiety-like behavior and excitability, as evidenced by prolonged inactivity, increased freezing episodes, preference for open space, reduced wall-rearing, and decreased grooming behavior. In later stages (day 10), a decline in exploratory activity and memory functions was observed, including a rise in errors in both reference and working memory tests. Administration of Pramistar and Noofen significantly reduced anxiety-related behaviors and exerted anti-amnestic effects (marked reduction in working memory errors), although no significant improvement was seen in learning capacity. Treatment with Melatonin, Cerebrocurin, Gliatilin, and Pronoran significantly reduced anxiety and excitability (decreased freezing, inactivity, and open space preference; increased wall-rearing and grooming), enhanced exploratory activity, demonstrated strong anti-amnestic effects (fewer errors in both memory types), and improved learning ability (increased active responses). Conclusions. The findings provide experimental support for the potential clinical use of these pharmacological agents in Parkinson’s disease. The studied compounds may offer effective correction of behavioral and cognitive-mnestic impairments during long-term PD therapy.

Traumatic brain injury is a major public health concern associated with significant neurological sequelae and high mortality. Although its treatment is multifactorial, the effects of amantadine hydrochloride—originally developed as an antiviral agent and later identified to have neuromodulatory properties—are still under investigation. This study aimed to evaluate the impact of amantadine hydrochloride on neurological outcomes in traumatic brain injury patients with different etiologies.A total of 51 patients diagnosed with traumatic brain injury of various etiologies and monitored in the intensive care unit were retrospectively included in the study. Sociodemographic data, clinical findings, imaging results, treatment details involving amantadine hydrochloride, and follow-up Glasgow Coma Scale scores were extracted from medical records. The mean age of the patients was 43.0±21.0 years, and 76.5% were female. The most common etiologies were subarachnoid hemorrhage (37.3%) and subdural hemorrhage (19.6%). Amantadine hydrochloride was administered to 50.9% of the patients. The need for sedation and anti-edema therapy was significantly higher in the amantadine group (p

18β-glycyrrhetinic acid-amantadine hybrid: Synthesis and anti-EMCV activity via NF-κB modulation.

Steady dimer formation by the S31N mutant of influenza A virus M2 protein in living cell membranes.

Parkinson's disease (PD) affects a large population worldwide with millions of people losing motor function control. Although there is no recognized cure for PD, current medications aim to manage the symptoms and slow down the progression of the disease. Amantadine is one such treatment option that can be used in both early and late stages of PD. The current study aimed to assess the relative bioequivalence of two test prototypes (Ta and Tb) of amantadine extended-release (ER) oral formulation manufactured by Sun Pharmaceuticals Industries Limited with the reference immediate-release (IR) formulation (R) of amantadine hydrochloride manufactured by Morton Grove Pharmaceuticals Inc. This was an open-label, balanced, randomized, three-treatment, six-sequence, three-period, single-dose once daily (OD) versus twice daily (BID), crossover relative bioavailability study in healthy adult male subjects under fasting condition with a total of 36 + 2 additional standby subjects meeting the eligibility criteria. The pharmacokinetic parameters including maximum concentration (Cmax), time to achieve Cmax (tmax), area under the plasma concentration-time curve from time zero to time t (AUC0-t), area under the concentration-time curve from 0 to 24 h (AUC0-24), area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞), and half-life (t1/2) were assessed. Statistical analysis was performed using analysis of variance (ANOVA) and ratio of least square means (LSM) (log transformed) was used to calculate the relative bioequivalence of the test drugs with the reference drug. Safety monitoring was done by considering adverse and serious adverse events during the duration of the study. Both Ta and Tb formulations demonstrated similar systemic exposure to the reference product, meeting the criteria for bioequivalence within acceptable limits (80.00-125.00%). The ratios of LSM for log-transformed pharmacokinetic parameters (90% confidence interval [CI]) for Ta versus R were 100.02% (96.75-103.40%) for Cmax, and 107.27% (102.75-112.00%) for AUC0-t; and for Tb versus R were 93.92% (90.38-97.60%) for Cmax, and 101.12% (96.73-105.71%) for AUC0-t. There were no adverse or serious adverse events observed during the study. These findings confirm the bioequivalence of the two test prototypes of amantadine ER formulation manufactured by Sun Pharmaceutical Industries Limited with the IRBID formulation of amantadine manufactured by Morton Grove Pharmaceuticals Inc. The pharmacokinetic equivalence supports the use of OD amantadine ER as an alternative to the BID IR formulation, with the potential to improve patient adherence due to reduced dosing frequency.

Cocrystallization of amantadine hydrochloride with nutrient: Insights into directed self- assembly and optimized biopharmaceutical character by integrating theory and experiment.

A novel one-step immunoassay using mesoporous core-shell Pd@Pt nanoparticles as an alternative to horseradish peroxidase for amantadine detection.

Lipid droplets (LDs) are dynamic organelles implicated in Parkinson's disease (PD) pathology, yet their polarity dynamics and therapeutic relevance remain poorly understood. Herein, we rationally designed a polarity-responsive alkenyl indole-based fluorophore, PD3, through systematic molecular engineering to enable real-time tracking of LD polarity in PD models. By modulating intramolecular charge transfer (ICT) effects via electron-donating/withdrawing substitutions, PD3 exhibited exceptional polarity sensitivity, with a dramatic fluorescence enhancement in low-polarity environments and negligible viscosity interference. Density functional theory calculations confirmed that the polarity response originated from ICT-driven solvatochromism and solvent-dependent internal conversion rates. In rotenone-induced PD cellular models, PD3 revealed significant LD accumulation (4.2-fold intensity increase, 74% higher LD density, and 46% enlarged diameter) and organelle crosstalk, particularly with the endoplasmic reticulum (ER) and mitochondria. Furthermore, PD3-enabled evaluation of PD drugs demonstrated that amantadine (AMA) and pramipexole (PPX) restored LD homeostasis, linking their therapeutic effects to LD modulation. Ex vivo studies in methyl-phenyl-tetrahydropyridine (MPTP)-induced PD mice confirmed LD accumulation in brain tissues, correlating with motor deficits and neuronal loss in the substantia nigra. This work establishes PD3 as a powerful tool for deciphering LD-associated PD pathology and advancing LD-targeted therapeutic strategies.

BackgroundMaternal viral infection during pregnancy can lead to maternal immune activation (MIA), increasing the risk of neurodevelopmental disorders in offspring. Amantadine (AMA) exhibits antiviral activity and is widely employed in the management of neurologic conditions. Nevertheless, the efficacy of AMA in treating MIA is currently not established.MethodsMIA was induced by polyinosinic acid–polycytidylic acid (poly(I:C)); AMA was administered from embryonic (E) day 11.5 for 3 days. BV‐2 cells were stimulated using poly(I:C) and treated with AMA. Behavior was assessed via open field test, elevated plus maze test, three‐chamber sociability test, and marble burying test. Neuronal morphology was vizualized using Nissl stain; apoptosis via TUNEL (terminal deoxynucleotidyl transferase dUTP nick‐end labeling) stain; protein expression (Iba1, NeuN, CD68, TNF‐α [tumor necrosis factor‐alpha], IL‐1β [interleukin‐1β]) using immunofluorescence (IF); interleukin‐6 (IL‐6) levels using enzyme‐linked immunosorbent assay; reactive oxygen species using staining; Iba1, NeuN, Bcl‐2, Bax, and cleaved caspase 3 using Western blot; and gene expression changes using RNA‐seq.ResultsAMA treatment reduced the levels of IL‐6 in maternal blood, improved autism‐like behaviors in MIA offspring, and effectively prevented neuronal damage and neuroinflammation. In vitro cellular studies have demonstrated that AMA effectively downregulates the expression levels of pro‐inflammatory cytokines, including IL‐6, TNF‐α, and IL‐1β. RNA‐seq analysis indicated that AMA mitigates abnormal activation of microglia by modulating inflammatory pathways associated with IL‐6.ConclusionAMA can prevent the development of neuropsychiatric disorders in MIA offspring. This effect may be related to its ability to attenuate neuronal damage, reduce neuronal apoptosis, and inhibit neuroinflammation, indicating that the antiviral drug AMA may be a potential treatment for MIA.

A rapid UPLC-MS/MS method was developed and validated for quantifying amantadine (AMD) and rimantadine (RIM) in human blood and urine. Sample preparation involved acetonitrile protein precipitation with amantadine-D6 as internal standard. Separation used an ACE C₁₈-PFP column and a mobile phase of 0.1% aqueous formic acid/5 mmol/L ammonium formate-acetonitrile (85:15, v/v). ESI⁺-MRM detection was employed. Acetonitrile provided optimal extraction. The method showed excellent linearity (1.0–1000.0 ng/mL; R² > 0.99), LOD/LOQ , mean recoveries (82.16–105.43%), and precision (RSD 3.57–10.39%). This sensitive, reliable method is suitable for forensic and public health applications.

Chitosan-coated nanostructured lipid carriers of amantadine for nose-to-brain delivery: formulation optimization, in vitro-ex vivo characterization, and in vivo anti-parkinsonism assessment.

Severe acute poisoning from Compound paracetamol and Amantadine hydrochloride tablets can result in various complications, including acute liver injury, central nervous system reactions, and gastrointestinal symptoms. A 15-year-old previously healthy female ingested 108 Compound paracetamol and Amantadine hydrochloride tablets. She presented to the emergency department with severe nausea, vomiting, abdominal pain, and distension, along with confusion. Emergency interventions, including gastric lavage and endotracheal intubation for respiratory support, were initiated. She was subsequently transferred to the intensive care unit for advanced life support, including nasogastric tube, hemoperfusion, and hemodialysis. During treatment, she developed coagulation abnormalities, liver injury, acute gastric mucosal bleeding, electrolyte imbalances, and psychiatric symptoms. A computed tomography (CT) scan revealed diffuse subcutaneous pneumatosis extending to the neck, anterior chest wall, thoracic cavity, and mediastinum. Following aggressive treatment, the patient was successfully discharged on the seventh day after the overdose. Acute liver injury and diffuse subcutaneous pneumatosis affecting multiple regions, caused by the ingestion of a large quantity of Compound paracetamol and Amantadine hydrochloride tablets, is a rare occurrence. With early gastric lavage, blood purification, and supportive therapy, the patient was successfully treated and discharged.

Glutamate (Gt) neurotoxicity is implicated in a wide range of neurological conditions, with the loss of glutamate transporters leading to intracellular Gt accumulation. Amantadine (AMn), a non-competitive N-Methyl-D-aspartate (NMDA) antagonist, can partially inhibit Gt transporters and modulate Protein Phosphatase 2A subunit B (PP-2A-B) activity. This study explores the potential of early-life AMn administration to counteract Gt-induced changes in the cerebral cortex using a rat model. Our findings indicate that AMn can reverse Gt-induced structural alterations in the brain cortex and enhance PP-2A activity. Additionally, PP-2A-B activity in the AMn+Gt-treated group was comparable to control levels. Furthermore, AMn administration reduced the apoptotic index in Gt-treated individuals. We propose that the severe histopathological changes observed in the Gt group may be attributed to decreased PP-2A expression, disrupting the balance between phosphatase and protein kinase activities and resulting in a strong positive TUNEL reaction. This study provides a concise overview of the current understanding of PP-2A-B’s role in Gt-induced neurotoxicity and AMn treatment while highlighting amantadine’s potential as a therapeutic agent. Keywords : Amantadine; Glutamate; cerebral cortex; PP-2A.

The increasing resistance of Candida albicans (C. albicans) to conventional antifungal drugs poses a great challenge to the clinical treatment of infections caused by this yeast. Drug combinations are a potential therapeutic approach to overcome the drug- resistance of C. albicans. This study explored the synergistic effects of amantadine hydrochloride (AMH) combined with azole antifungal drugs against drug-resistant C. albicans in vitro and in vivo. The in vitro sensitivity of Candida spp. to drugs was determined by the microdilution method. The effect of drugs on the efflux pump activity of C.albicans was determined by the rhodamine 6G tracer method. The egg yolk agar plate method was used to determine the activity of extracellular phospholipase, a C. albicans virulence factor. The Galleria mellonella modelofC. albicans infection was used to test the in vivo efficacy of the combination therapy. In vitro experiments showed that combinations of AMH with azole antifungal drugs had synergistic antifungal effects on planktonic cells of drug-resistant C. albicans, with fractional inhibitory concentration index values of <0.5. The in vivo synergistic effects and mechanism of drug combinations with AMH were further studied using fluconazole (FLC) as a representative azole antifungal drug. In vivo, G. mellonella larvae were used to evaluate the antifungal efficacy of AMH +FLC. AMH + FLC treatment increased the survival rate of larvae infected with drug-resistant C. albicans and reduced tissue invasion. Studies of the mechanism of synergy showed that AMH inhibited drug efflux pump activity in drug-resistant C. albicans, and that AMH + FLC synergistically inhibited early biofilms and the extracellular phospholipase activity of drug-resistant C. albicans. This study provides strong evidence that combinations of non-antifungal drugs and antifungal drugs can effectively overcome drug-resistant C.albicans infection. Both AMH and FLC are FDA-approved drugs, eliminating concerns about safety. Our findings provide a foundation for further clinical antifungal research.

Detecting amantadine (AMD) residues in food is essential due to its illegal use in livestock for disease prevention and growth promotion, practices that can lead to harmful drug residues in meat, eggs, and milk. Such residues pose significant public health concerns, including the development of drug-resistant pathogens. In this study, a highly sensitive and selective fluorometric method is presented for detecting AMD in food matrices. The assay is based on the formation of a fluorescent isoindole derivative via a ternary reaction between o-phthalaldehyde (OPA), the primary amine group of AMD, and dithiothreitol (DTT) on citrate-stabilized gold nanoparticles (C-AuNPs) functionalized with DTT (DTT@C-AuNPs) under alkaline conditions. DTT acts as a bifunctional linker, anchoring to the nanoparticle surface through one SH group, while the second SH remains available to participate in isoindole formation. This configuration results in a turn-on fluorescence system, with emission observed at λex = 330 nm and λem = 460 nm, overcoming the typical quenching associated with AuNPs-based sensors. The method demonstrated LOD of 20 nM and high anti-interference/selectivity toward AMD, with minimal interference from matrix components. Validation through standard addition recovery experiments in AMD-spiked food samples confirmed the assay's accuracy and precision. Overall, this fluorometric platform offers a rapid, reliable, and cost-effective approach for AMD monitoring, supporting its practical application in food quality control and regulatory surveillance programs.

Supramolecular fluorescent materials with switchable behavior and induced luminescence enhancement are a new class of special materials for constructing fluorescence anti-counterfeiting materials. Since these materials are constructed by self-assembly through supramolecular host-guest interactions of non-covalent bonds, such fluorescent materials can regulate their optical properties through a reversible assembly-disassembly process. Inspired by the role of the β-barrel scaffold in activating strong fluorescence of a green fluorescent protein (GFP) chromophore, we designed a supramolecular system based on a novel GFP analogue (CA) and cucurbit[7]uril (CB[7]). CA molecules are encapsulated by CB[7] to form a 1 : 2 host-guest assembly, thereby the fluorescence brightness of CA can be tuned. The reversible regulation of fluorescence intensity was additionally realized by controlling the dynamic assembly-disassembly process in the presence of a higher binding competitor, amantadine hydrochloride. The CA-CB[7] system was successfully used for information anti-counterfeiting through the reversible fluorescence readout on A4 paper, which enables the GFP chromophore analogue and cucurbituril system to become a potential candidate for constructing intelligent information encryption and anti-counterfeiting materials.

Brain trauma-induced cytokine storms can impact multiple organs, particularly the heart, through inflammatory and apoptotic mechanisms. This study aimed to examine cardiac pathology following experimental brain trauma (BTCI) and evaluate the protective effects of amantadine (AMN), an NMDA receptor antagonist, on cardiotoxicity. Forty rats were divided into four groups: sham, BTCI, BTCI+AMN-1 (45 mg/kg, ip), and BTCI+AMN-7. Trauma (0.2 Newton) was induced by dropping a 50 g ball from 80 cm. Heart samples were collected 24 hours and seven days post-trauma for histopathological and immunohistochemical analysis. The BTCI group showed hyperemia, hemorrhage, inflammatory infiltrations, increased Bax and VCAM expressions, and decreased Bcl-2 expression. AMN treatment reversed these findings, with greater efficacy observed after seven days. In conclusion, BTCI induces cardiac damage, while AMN provides protective effects. Further studies are needed to clarify underlying mechanisms.