Application of cocoa butter for formulation of fast melt tablets containing memantine hydrochloride.

INTRODUCTION: Fast melt tablets (FMTs) provide a convenient dosage form that rapidly dissolves on the tongue without the need for water. Cocoa butter serves as a suitable matrix system for FMTs formulation, facilitating rapid disintegration at body temperature. OBJECTIVES: This study aimed to formulate FMTs using cocoa butter as a base and investigate the effect of various disintegrants and superdisintegrants on their characteristics. METHODS: Cocoa butter-based FMTs were prepared via the fusion molding technique. Different disintegrants and superdisintegrants were added at varying concentrations and subjected to characterization. The optimal formulation was selected and incorporated with 10 mg memantine hydrochloride. RESULTS: The optimal FMT formulation consisted of 340 mg cocoa butter, 75 mg starch, and 75 mg crospovidone, exhibiting a hardness of 17.12 ± 0.31 N and a disintegration time of 32.67 ± 0.17 s. Furthermore, FMTs demonstrated a faster release profile compared to the commercially available product, Ebixa. SEM micrographs revealed homogenous blending of individual ingredients within the cocoa butter matrix and FT-IR analysis confirmed the chemical stability of memantine hydrochloride in the formulation. The dissolution profile of F17 suggested that the drug in FMTs released faster compared to Ebixia. Memantine hydrochloride achieved 98.07% of drug release in FMTs at 10 min. Moreover, the prepared FMTs exhibited stability for at least 6 months. CONCLUSION: The successful development of cocoa butter-based FMTs containing memantine hydrochloride highlights the potential of cocoa butter as viable alternative matrix-forming material for FMTs production. This innovative formulation offers patients a convenient alternative for medication administration.

Combined treatment of methylprednisolone pulse and memantine hydrochloride prompts recovery from neurological dysfunction and cerebral hypoperfusion in carbon monoxide poisoning: a case report.

A 49-year-old healthy man developed sudden unconsciousness under inadequate ventilation. Blood gas analysis showed carboxyhemoglobin of 7.3%. After normobaric oxygen therapy, he recovered completely 7 days later. At 3 weeks after carbon monoxide (CO) exposures, memory and gait disturbances appeared. Neurological examination revealed Mini-Mental State Examination (MMSE) score of 5 of 30 points, leg hyper-reflexia with Babinski signs, and Parkinsonism. Brain fluid-attenuated inversion recovery imaging disclosed symmetric hypointense lesions in the thalamus and the globus pallidus, and hyperintense lesions in the cerebral white matter. Brain single-photon emission tomography (SPECT) scanning with (99m)Technesium-ethyl cysteinate dimer displayed marked hypoperfusion in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. He was diagnosed as CO poisoning and treated with hyperbaric oxygen therapy. The neurological deficits were not ameliorated. At 9 weeks after neurological onset, methylprednisolone (1000 mg/day, intravenous, 3 days) and memantine hydrochloride (20 mg/day, per os) were administered. Three days later, MMSE score was increased from 3 to 20 points. Neurological examination was normal 3 weeks later. Brain SPECT exhibited 20% increase of regional cerebral blood flows in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. These clinicoradiological changes supported that the treatment with steroid pulse and memantine hydrochloride could prompt recovery from neurological dysfunction and cerebral hypoperfusion. Further clinical trials are warranted whether such combined therapy can attenuate neurological deficits and cerebral hypoperfusion in patients with CO poisoning.

Mitigating radiation-induced brain injury via NLRP3/NLRC4/Caspase-1 pyroptosis pathway: Efficacy of memantine and hydrogen-rich water.

Radiation-induced brain injury (RIBI) is a significant challenge in radiotherapy for head and neck tumors, impacting patients' quality of life. In exploring potential treatments, this study focuses on memantine hydrochloride and hydrogen-rich water, hypothesized to mitigate RIBI through inhibiting the NLRP3/NLRC4/Caspase-1 pathway. In a controlled study involving 40 Sprague-Dawley rats, divided into five groups including a control and various treatment groups, we assessed the effects of these treatments on RIBI. Post-irradiation, all irradiated groups displayed symptoms like weight loss and salivation, with notable variations among different treatment approaches. Particularly, hydrogen-rich water showed a promising reduction in these symptoms. Histopathological analysis indicated substantial hippocampal damage in the radiation-only group, while the groups receiving memantine and/or hydrogen-rich water exhibited significant mitigation of such damage. Molecular studies, revealed a decrease in oxidative stress markers and an attenuated inflammatory response in the treatment groups. Immunohistochemistry further confirmed these molecular changes, suggesting the effectiveness of these agents. Echoing recent scientific inquiries into the protective roles of specific compounds against radiation-induced damages, our study adds to the growing body of evidence on the potential of memantine and hydrogen-rich water as novel therapeutic strategies for RIBI.

Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?

BACKGROUND: Chikungunya fever is an endemic disease caused by the Chikungunya virus (CHIKV) to which there is no vaccine or effective antiviral drug treatment so far. Our study aimed to evaluate the potential anti-CHIKV activity of memantine hydrochloride (mtnH), a drug from the class of the aminoadamantanes approved for the treatment of Alzheimer´s disease, as a possible drug to be repurposed to the treatment of Chikungunya fever. METHODS: MtnH antiviral activity against CHIKV was determined by infecting BHK-21 cells with CHIKV-nanoluc, a virus carrying the marker nanoluciferase reporter, in the presence or absence of mtnH at concentrations ranging from 500 to 1.45 µM. The effective concentration of 50% inhibition (EC50) was calculated. Cell viability assay (determination of CC50) was also performed employing BHK-21 cells. Mutagenic assays were performed by the Salmonella Typhimurium/microsome assay (Ames test). RESULTS: MtnH presented a CC50 of 248.4 ± 31.9 µM and an EC50 of 32.4 ± 4 µM against CHIKV in vitro. The calculated selectivity index (SI) was 7.67. MtnH did not induce genetic mutation in Salmonella strains with or without an external metabolizing system. CONCLUSION: With the data herein presented, it is possible to hypothesize mtnH as a viable candidate to be repurposed as an anti-CHIKV drug. Clinical assays are, therefore, encouraged due to the promising in vitro results. The drug memantine hydrochloride is herein personified with a doubt: as a prior regulated drug against Alzheimer, could it follow the path against Chikungunya virus too?

Cerebralcare Granule® enhances memantine hydrochloride efficacy in APP/PS1 mice by ameliorating amyloid pathology and cognitive functions.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Current drugs can only relieve symptoms, but cannot really cure AD. Cerebralcare Granule® (CG) is a Traditional Chinese medicine (TCM) containing a variety of biologically active compounds. In our previous studies, CG has shown a beneficial effect against memory impairment in mice caused by D-galactose. However, whether CG can be used as a complementary medicine for the treatment of AD remains unexplored. Here, we use a combination of CG and memantine hydrochloride (Mm) to treat Alzheimer-like pathology and investigate the effects and mechanisms in vivo. METHODS: The histology of brain was examined with Hematoxylin-eosin (HE) staining, Golgi staining and Thioflavin S staining. ELISA was applied to assess the expression levels or activities of CAT, SOD, GSH-Px, MDA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL) in serum, as well as the levels of IL-6, IL-1ß, and TNF-α in the mice brain. Western blotting was used to assess the expression of ß-secretase (BACE1), amyloid precursor protein (APP), APPß, APPα, synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95). RESULTS: In the present study, the combination group (CG + Mm) significantly attenuated Alzheimer-like behavior without adverse effects in APP/PS1 mice, indicating its high degree of safety and efficacy after long-term treatment. CG + Mm reduced AD pathological biomarker Aß plaque accumulation by inhibiting BACE1 and APP expression (P < 0.05 or P < 0.001). Besides, the combination group markedly inhibited the levels of IL-1ß, IL-6, and TNF-α in hippocampus (P < 0.001), as well as activities of SOD, CAT, and GSH-Px in serum (P < 0.001). By contrast, the combination group improved synaptic plasticity by enhancing SYN, PSD95, and GAP43 expression. CONCLUSIONS: Taken together, these data supported the notion that CG combined with Mm might ameliorate the cognitive impairment through multiple pathways, suggesting that CG could play a role as complementary medicine to increase anti-AD effect of chemical drugs by reducing Aß deposition, neuroinflammation, oxidative damage, and improving synaptic plasticity.

[The use of Akatinol Memantine in the treatment of gait disturbances in Parkinson's disease]. / Vliyanie Akatinola Memantina na narusheniya khod'by na razvernutykh stadiyakh bolezni Parkinsona.

OBJECTIVE: To assess the efficacy of memantine hydrochloride in the treatment of GD in PD patients. MATERIALS AND METHODS: Patients of the main group (n=30) received memantine hydrochloride (akatinol memantine) in a dose of 20 mg/day for 3 months in addition to antiparkinsonian therapy. Patients of the comparison group (n=25) received only antiparkinsonian drugs. Cognitive rating scales and computerized gait assessment protocol were performed in both groups twice in 3 months interval in order to examine cognitive deficit and gait parameters. RESULTS: The increase in MMSE scores, improvement in gait cycle phases ratio and increase of cadence according to computerized gait analysis were observed in the main group compared to the comparison group. CONCLUSION: The improvement in gait achieved during the study confirms that the treatment of cortical gait disturbances in patients with PD using memantine hydrochloride is a promising area of therapy.

A rapid FTIR spectroscopic assay for quantitative determination of Memantine hydrochloride and Amisulpride in human plasma and pharmaceutical formulations.

A selective, new, rapid and nondestructive Fourier transform Infrared spectroscopic assay has been developed for simultaneous determination of Memantine hydrochloride and Amisulpride in human plasma and their pharmaceutical formulations without interference from common dugs excipients. A binary mixture of ME and nonselective ß-blocker namely; carvidalol has been determined the solid-state by FTIR spectroscopy for the first time. The linear range had been extent from 1.0 to 8.0 and 1.0 to 10.0 µg/mg, for ME and AMS respectively. The detection limits were 0.29 and 0.23 µg/mg while quantitation limits were 0.90 and 0.71 µg/mg for ME and AMS respectively. The developed assay has been validated according to ICH & USP recommendations and successfully applied for quantitative determination of selected drugs in biological fluid.

A new spectrofluorimetric assay for quantification of Amisulpride and Memantine hydrochloride in real human plasma sample and pharmaceutical formulations via Hantzsch reaction.

A new, selective and accurate spectrofluorimetric assay has been described for detection of Amisulpride and Memantine hydrochloride in pharmaceutical formulations and real plasma samples. The described assay depends on the reaction between the primary amino group of the selected drugs with acetyl acetone & formaldehyde in an acetate buffer of pH4.8. The derivatized product showed yellow fluorescence at λex=418nm and λem=484.5nm. The calibration graph was linear in the range of 0.05-0.5 and 0.2-1µgmL-1 for AMS and ME, orderly. The limits of detection were 0.0085 and 0.0153µgmL-1, and the limits of quantitation were 0.026 and 0.0464µgmL-1 for AMS and ME respectively. Validation of the described assay was in consonance with ICH guideline. Due to the sensitivity of the prescribed assay, it permits the determination of selected medications in biological sample quantitatively.

Utility of chromogenic property of 2, 2-dihydroxyindane-1, 3-dione for quantification of Memantine hydrochloride in pure, pharmaceutical preparation and application to uniformity testing.

Accurate, simple, sensitive, and fast spectrophotometric assay was applied for the quantification of certain anti-Alzheimer drug namely; Memantine hydrochloride, in its bulk and pharmaceutical preparation. The described assay has been established on the reaction between the primary amino moiety of the cited drug and 2,2-dihydroxyindane-1,3-dione reagent in N,N'-dimethylformamide medium in boiling water bath. Which give Ruhemann's purple color that can be determined at λmax = 595 nm. Beer's law has been obeyed within drug concentration range from 10-120 µg per milliliter. Detection limit and quantitation limit have been 1.6 & 4.9 µg per milliliter respectively. Developed procedure has been validated in agreement with International Conference of Horizon recommendations and applied successfully for detection of cited drug in bulk, pharmaceutical dosage form and content uniformity testing.

[Modern views on gait impairment in Parkinson`s disease and its correction]. / Sovremennye predstavleniia o narusheniiakh khod'by pri bolezni Parkinsona i metodakh ikh korrektsii.

The article reviews the causes of gait impairment in patients with Parkinson's disease (PD). The emphasis is made on modern ideas, according to which gait impairment in PD is caused by a multisystem lesion and non-dopaminergic dependent mechanisms play the leading role. It is highlighted that gait impairment in PD is associated with the disruption of frontal/subcortical neural pathways which requires a special approach to pharmacological and non-pharmacological therapy. Based on pathogenetic mechanisms, much attention is paid to anti-dementia medications. Attention is drawn to the fact that the use of memantine hydrochloride (akatinol memantine) is a promising direction for gait impairment correction in the advanced and late stages of PD due to the improvement of glutamatergic transfer from the striatum to the specific areas of the cerebral cortex involved in gait control. The results of the latest clinical trials are analyzed.

Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma.

Glioblastoma is one of the most aggressive malignant primary brain cancer in adults. To date, surgery, radiotherapy and current pharmacological treatments are not sufficient to manage this pathology that has a high mortality rate (median survival 12-15months). Recently, anticancer multi-targeted compounds have attracted much attention with the aim to obtain new drugs able to hit different biological targets that are involved in the onset and progression of the disease. Here, we report the synthesis of novel memantine-derived drugs (MP1-10) and their potential antitumor activities in human U87MG glioblastoma cell line. MP1-10 were synthetized joining memantine, which is a NMDA antagonist, to different histone deacetylase inhibitors to obtain one molecule with improved therapeutic efficacy. Biological results indicated that MP1 and MP2 possessed more potent anti-proliferative effects on U87MG cells than MP3-10 in a dose-dependent manner. MP1 and MP2 induced significant cell death by apoptosis characterized by apoptotic morphological changes in Hoechst staining. Both drugs also exhibited non-genotoxic and only mild cytotoxic effects in human whole blood cells. However, only MP1, showing good chemico-physical properties (solubility, LogP) and enzymatic stabilities in gastric and intestinal fluids, can be considered a suitable candidate for in vivo pharmacokinetic studies.

Post-injury administration of a combination of memantine and 17ß-estradiol is protective in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) often leads to substantial adverse cognitive and health outcomes, including permanent disability and death. Preventing these outcomes requires attenuation of the secondary biochemical damage that follows the initial biomechanical insult, but a clinically proven pharmacotherapeutic capable of such has not been identified. In fact, the heterogeneous nature of TBI and the complexity of secondary injury cascades suggest a polytherapeutic approach that targets multiple pathways might be necessary. We and others have reported that 17ß-estradiol (E2) is neuroprotective in models of central nervous system injury. Although E2 is neuroprotective and favorably modulates several key components of secondary injury, it does not effectively block the destructive excitotoxic cascade. Thus, administering E2 in combination with a second drug that targets excitotoxicity, such as the FDA-approved uncompetitive NMDA receptor antagonist memantine hydrochloride, may provide additional benefits. Here, we assessed the neuroprotective potential of an acutely administered intravenous bolus dose of a combination of memantine and E2 after induction of experimental TBI in the clinically relevant lateral fluid percussion model. Our results indicate that the combination of these drugs conferred neuroprotection by increasing neuronal survival and decreasing neuronal degeneration in the hippocampus and cortex ipsilateral to injury. Furthermore, administration of this combination improved vestibulomotor deficits and modestly reduced anxiety. We conclude that further investigation of the neuroprotective potential of memantine administered with E2 is warranted.

A new simultaneous derivatization and microextration method for the determination of memantine hydrochloride in human plasma.

A simple and sensitive method for simultaneous derivatization and hollow fiber liquid phase microextraction (HF-LPME) followed by high performance liquid chromatography-fluorescence detection (HPLC-FL) to determine memantine hydrochloride (MT) in human plasma was developed. The derivatization and microextraction was combined to a single step to ensure the precision. What is more, the derivatization reaction accelerated the mass transfer during the process of microextraction. The hollow fiber was filled with cyclohexane and dansyl chloride (derivatization agent) as acceptor phase and submersed in the alkalinized plasma sample. The system was submitted to stirring at 800rpm for 50min at 40°C. Different experimental parameters were systematically evaluated by response surface methodology. Under the optimized conditions, the calibration curve was linear in the range of 1-100ng/mL (r=0.9991) with a limit of detection of 0.1ng/mL (S/N=3). The precision estimated as the relative standard deviation (RSD) was less than 4.5% and the accuracy was 94.3-100.7%. The present method was successfully applied to determine MT in human plasma samples.

Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression.

Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 µM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 µM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 µM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 µM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 µM) and MK801 (10 µM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.

A Validated Stability-indicating Reverse Phase HPLC Assay Method for the Determination of Memantine Hydrochloride Drug Substance with UV-Detection Using Precolumn Derivatization Technique.

This present paper deals with the development and validation of a stability indicating high performance liquid chromatographic method for the quantitative determination of Memantine hydrochloride. Memantine hydrochloride was derivatized with 0.015 M 9-fluorenylmethyl chloroformate (FMOC) and 0.5 M borate buffer solution by keeping it at room temperature for about 20 minutes and the chromatographic separation achieved by injecting 10 muL of the derivatized mixture into a Waters HPLC system with photodiode array detector using a kromasil C18 column (150 x 4.6 mm), 5 mu. The mobile phase consisting of 80% acetonitrile and 20% phosphate buffer solution and a flow rate of 2 milliliter/minute. The Memantine was eluted at approximately 7.5 minutes. The volume of FMOC used in derivatization, concentration of FMOC and derivatization time was optimized and used. Forced degradation studies were performed on bulk sample of Memantine hydrochloride using acid (5.0 Normal (N) hydrochloric acid), base (1.0 N sodium hydroxide), oxidation (30% hydrogen peroxide), thermal (105 degrees C), photolytic and humidity conditions. The developed LC method was validated with respect to specificity, precision (% RSD about 0.70%), linearity (linearity of range about 70-130 mug/mL), ruggedness (Overall % RSD about 0.35%), stability in analytical solution (Cumulative % RSD about 0.11% after 1450 min.) and robustness.