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Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At present, implementation of effective treatment approaches for AD is vital to meetclinical needs. In AD research, priorities concern the development of disease-modifying therapeutic agents to be used in the early phases of AD and the optimization of the symptomatic treatments predominantly dedicated to the more advanced AD stages. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. In case of AD, CT is more effective, mostly when started early, at slowing the rate of cognitive impairment. In this review, we have covered the major studies regarding CT to combat AD pathogenesis. Moreover, we have also highlighted the safety, tolerability, and efficacy of CT in the treatment of AD.

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.

The NMDA ( N -methyl- d -aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel 1 . Owing to the lack of high-resolution structural studies of the NMDA receptor, the mechanism by which ion-channel blockers occlude ion permeation is not well understood. Here we show that removal of the amino-terminal domains from the GluN1–GluN2B NMDA receptor yields a functional receptor and crystals with good diffraction properties, allowing us to map the binding site of the NMDA receptor blocker, MK-801. This crystal structure, together with long-timescale molecular dynamics simulations, shows how MK-801 and memantine (a drug approved for the treatment of Alzheimer’s disease) bind within the vestibule of the ion channel, promote closure of the ion channel gate and lodge between the M3-helix-bundle crossing and the M2-pore loops, physically blocking ion permeation. A high-resolution X-ray structure and molecular dynamics simulations of the N -methyl- d -aspartate receptor in complexes with channel-blocking ligands reveals the molecular basis of the ligand binding and channel block.

The smartphone-based colorimetric approach has emerged as a powerful analytical tool with broad applications, enabling fast and cost-effective measurements, eco-friendly operation with low energy demand, and reasonable analytical performance. In this work, a simple and eco-friendly colorimetric method was developed for the determination of memantine (MEM) in pharmaceutical dosage forms. In this approach, MEM reacts with ascorbic acid to produce a pink-colored product exhibiting two absorption maxima (λ_max) at 386 nm and 530 nm. The color response was captured using a smartphone camera and analyzed digitally with ImageJ software, where the extracted color intensity values were correlated with MEM concentration. A conventional spectrophotometric method relying on the absorbance at 386 nm was also established. Both methods exhibited excellent linearity over the concentration range of 5.0–50.0 µg/mL. The smartphone-based method showed a limit of detection (LOD) of 0.45 µg/mL and limit of quantitation (LOQ) of 1.36 µg/mL, while the spectrophotometric method exhibited a LOD of 0.0615 µg/mL and LOQ of 0.19 µg/mL. The greenness of the methods was evaluated using the newly introduced EPPI tool, a comprehensive metric that assesses greenness, applicability, and analytical performance. The results are presented as pie charts and numerical scores. The total scores for the smartphone and colorimetric approaches were 84.4 and 82.4, respectively, indicating the superiority of the smartphone-based method in terms of sustainability and practical applicability.

Topological indices, which are numerical descriptors that encode molecular structure, are widely used in computational drug discovery due to their efficiency and interpretability. In this study, we developed a robust quantitative structure–property relationship (QSPR) framework to predict the core physicochemical properties of nine clinically relevant Alzheimer’s disease drugs, including Donepezil, Galantamine, and Memantine.​ We employed a streamlined computational approach, using MATLAB and the M-polynomial method, to efficiently calculate a series of degree-based topological indices. Through comprehensive regression analyses, we identified strong correlations between degree-based topological indices and key physicochemical properties, including boiling point and molar refractivity. While linear models provided a reasonable baseline, nonlinear models, particularly cubic and power equations, delivered significantly improved predictive accuracy. The analysis highlighted the critical interplay between the choice of the index and the regression model. For instance, the cubic model was frequently the most effective for predicting properties such as boiling point and flash point, while the power model performed best for molar refractivity and polarizability. Notably, the redefined first Zagreb index and the modified first Zagreb index exhibited exceptional predictive capacity, reflecting their sensitivity to structural features that govern physicochemical behavior. The strong performance of these QSPR models underscores their potential to accelerate the rational design of Alzheimer’s therapeutics. By enabling rapid, cost-effective, and reliable property prediction prior to synthesis, this framework offers a valuable tool for future drug development efforts.

A zone-fluidics (ZF) based automated fluorimetric sensor for the determination of pharmaceutically active adamantine derivatives, i.e., amantadine (AMA), memantine (MEM) and rimantadine (RIM) is reported. Discrete zones of the analytes and reagents (o-phthalaldehyde and N-acetylcysteine) mix and react under stopped-flow conditions to yield fluorescent iso-indole derivatives (λex/ λem = 340/455 nm). The proposed ZF sensor was developed and validated to prove suitable for quality control tests (assay and content uniformity) of commercially available formulations purchased from the Greek market (EU licensed) and from non-EU web-pharmacies at a sampling rate of 16 h−1. Interestingly, a formulation obtained through the internet and produced in a third—non-EU—country (AMA capsules, 100 mg per cap), was found to be out of specifications (mean assay of 85.3%); a validated HPLC method was also applied for confirmatory purposes.

Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer’s disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer’s disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM.

New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized. It was found that, in addition to the ability to block the intrachannel site of NMDA receptors, the new hybrid compounds exhibit the property of blockers of the allosteric site of NMDA receptors, which is not inherent in memantine and edaravone preparations. The most active hit compound was determined, which, along with the properties of a two-site blocker of the NMDA receptor, exhibits a pronounced activity as an inhibitor of lipid peroxidation, similarly to the drug edaravone.

The case Federal Trade Commission v Actavis, which went to the Supreme Court last year, 2 examined the issue of reverse payment patent settlements, also known as pay to delay agreements, in which the branded drug maker sues a prospective generic competitor for patent infringement then reaches a settlement in which the plaintiff pays a generous sum to the defendant to stay out of the market, allowing the branded maker to continue to occupy that market segment at its higher price.

The objectives of this study were to characterize sepia, synthetic, and bovine melanin and to determine their binding characteristics to the drug memantine. Physical methods were used to characterize sepia, synthetic, and bovine melanin. Their binding properties toward memantine were determined in deionized water and phosphate-buffered saline (PBS) at 37 degrees C. Melanin-memantine binding was measured indirectly by determining the unbound fraction of memantine. Curve fitting according to the Langmuir binding isotherm for one binding site was used for the determination of binding capacity (BLmax) and dissociation constant (KD). Synthetic and sepia melanin had comparable Gaussian particle size distributions, whereas bovine melanin showed a heterogeneous distribution profile. The suspension medium had a small effect on the particle size distribution of synthetic and bovine melanin. There were characteristic differences in the infrared spectra of the melanins. The rank order for BLmax in deionized water was sepia > bovine > synthetic melanin. However, when the melanins were suspended in PBS, the BLmax values were lower, and the rank order was bovine > sepia > synthetic. Whereas the KD values for sepia and synthetic melanin remained largely the same in deionized water and PBS, the KD value for bovine melanin in PBS was more than twice than in deionized water. This study showed that the physical characteristics of the melanins investigated differ markedly. The binding of memantine to melanin is thought to be determined by the different chemistries of the melanins, particle size, and buffer electrolytes.