Memantine

179.3

179.30

1308068-626-2

W8O17SJF3T

DTXSID5045174

Oil

N06DX01|N - Nervous system

2921300090

26

3.5

Solid

1.046

258 °C

239.8±8.0 °C(Predicted)

92.3±9.7 °C

nD25 1.4941

4.55e-02 g/L

Store at RT

1.9X10-4 mm Hg at 25 deg C (est)

10.27None

Henry's Law constant = 1.47X10-5 atm-cu m/mole at 25 °C (est)

10.27|pKa = 10.7 (est)

Hydroxyl radical reaction rate constant = 3.34X10-11 cu cm/molec-sec at 25 °C (est)

24/25

Xi

Stable under recommended storage conditions.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Incompatible materials: Strong oxidizing agents

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including memantine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Memantine hydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory.

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Skin protection: Handle with gloves.|Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapours, mist or gas.; Environmental precautions: Do not let product enter drains.; Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.

Memantine was present in 88% of effluent samples from 90 European wastewater treatment plants at an average concentration of 22.8 ng/L; median concentration 3.7 ng/L, maximum concentration 1312 ng/L, limit of quantitation 0.5 ng/L. The samples were from plants in Austria, Belgium, Czech Republic, Cyprus, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Netherlands, Portugal, Slovenia, Spain, Sweden and Switzerland. Sampling was conducted in 2010(1).

**LD50** Oral LD50, mouse 437-498 mg/kg Oral LD50, rat 328-370 mg/kg **Carcinogenesis, Mutagenesis, Impairment of Fertility** No evidence of carcinogenicity was seen in mouse and rat models administered memantine at doses equivalent to supratherapeutic human doses. Additionally, no genotoxic potential was noted when a battery of assays was performed. No effects on fertility or reproductive performance were noted in rats given to 18 mg/kg/day (equivalent to 9 times the maximum recommended human dose) orally from 14 days preceding mating through gestation and lactation in females, or for 60 preceding mating activity in males animals. **Use in pregnancy** This drug is considered a pregnancy category B drug, meaning no sufficiently controlled and adequate studies of memantine in pregnant women have been performed. This drug should be taken during pregnancy only if the potential benefit justifies the possible fetal risk. **Use in nursing** It is unknown whether memantine is excreted in human milk. Due to that fact that many drugs are found excreted in human milk, caution should be observed when this drug is taken by a nursing mother.|IDENTIFICATION AND USE: Memantine is an oil. It is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor. HUMAN EXPOSURE AND TOXICITY: Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. Renal impairment and hyperkalaemia possibly associated with memantine administration was described in one patient. Two cases of repeated loss of consciousness were reported after long-term memantine treatment in patients with Alzheimer disease, which resolved after its discontinuation. Little is known about the cardiovascular effects of memantine but there have been reports of bradycardia and reduced cardiovascular survival associated with its use. Memantine produced no evidence of genotoxic potential in vitro in chromosomal aberration test in human lymphocytes. ANIMAL STUDIES: In newborn mice treatment with memantine temporally improves hippocampus-dependent memory formation. In rats memantine administration significantly attenuated the ethanol-associated behavioral alterations in a dose-dependent manner. Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, or in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

In large placebo controlled trials, the rate of serum enzyme elevations during memantine therapy was similar to that in patients on placebo and no instances of clinically apparent liver injury were reported. Nevertheless, since its introduction into clinical use, memantine has been implicated in at least one report of clinically apparent hepatotoxicity. The time to onset was 3 weeks and the clinical syndrome was that of an acute cholestatic hepatitis which was mild-to-moderate in severity and rapidly reversible upon drug discontinuation (Case 1). Immunoallergic and autoimmune features were not present.

Protein-bound Drugs: Because plasma protein binding of memantine is low (45%), a pharmacokinetic interaction with drugs that are highly protein bound (e.g., digoxin, warfarin) is unlikely.|Drugs Secreted by Renal Tubular Cationic Transport: Potential pharmacokinetic interaction (altered plasma concentrations of both drugs) when memantine is used with drugs secreted by the same renal cationic system (e.g., cimetidine, hydrochlorothiazide, metformin, nicotine, quinidine, ranitidine, triamterene). However, concomitant use of memantine with a fixed combination of hydrochlorothiazide and triamterene did not affect bioavailability of either memantine or triamterene, and maximum plasma concentrations and area under the plasma concentration-time curve (AUC) of hydrochlorothiazide decreased by only 20%. In addition, concomitant use of memantine with a fixed combination of glyburide and metformin hydrochloride did not affect the pharmacokinetics of memantine, metformin, or glyburide, and the hypoglycemic effects of the glyburide-metformin combination were not affected.|Alkalinizing Agents: Potential decreased memantine clearance with resulting increases in adverse effects when drug is used concomitantly with agents that increase urine pH (e.g., carbonic anhydrase inhibitors, sodium bicarbonate). Use with caution. Memantine clearance was decreased by approximately 80% at alkaline urine conditions (ie, pH 8).|Cholinesterase Inhibitors: Concomitant use of memantine with the acetylcholinesterase inhibitor donepezil did not affect the pharmacokinetics of either drug or substantially alter acetylcholinesterase inhibition by donepezil. In a 24-week clinical study in patients with moderate to severe Alzheimer's disease, adverse effects observed with combination therapy with memantine and donepezil were similar to those observed with donepezil alone. In vitro and animal studies indicate that memantine does not affect the reversible inhibition of acetylcholinesterase produced by donepezil, galantamine, or tacrine.|For more Interactions (Complete) data for MEMANTINE (9 total), please visit the HSDB record page.

The protein binding for memantine is about 45%.

Memantine's production and administation as an antiparkinsonian and antispasmodic drug(1) and to treat dementia associated with Alzheimer disease(2) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 660(SRC), determined from a structure estimation method(2), indicates that memantine is expected to have very low mobility in soil(SRC). The estimated pKa of memantine is 10.7(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Memantine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 660(SRC), determined from a structure estimation method(2), indicates that memantine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 10.7(3) indicates memantine will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water and moist soil surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 70(SRC), from its log Kow of 3.28(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2015).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), memantine, which has an estimated vapor pressure of 1.9X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase memantine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hrs(SRC), calculated from its rate constant of 3.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Memantine does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of memantine with photochemically-produced hydroxyl radicals has been estimated as 3.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Memantine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Memantine does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 70 was calculated in fish for memantine(SRC), using a log Kow of 3.28(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of memantine can be estimated to be 660(SRC). According to a classification scheme(2), this estimated Koc value suggests that memantine is expected to have low mobility in soil. The estimated pKa of memantine is 10.7(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

The estimated pKa of memantine is 10.7(1), indicating that this compound will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces is not expected to be an important fate process. Memantine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-4 mm Hg(SRC), determined from a fragment constant method(2).

Occupational exposure to memantine may occur through inhalation and dermal contact with this compound at workplaces where memantine is produced or used. The general public is not likely to be exposed to memantine unless by direct medical treatment. (SRC)

Memantine is used to manage moderate to severe Alzheimer's dementia. A more recent systemic review and meta-analysis indicates that memantine is beneficial as a first line drug for the treatment of Alzheimer's dementia. Cholinesterase inhibitors may be added to memantine for further beneficial effects on behavioral symptoms and other symptoms of dementia.|FDA Label|Treatment of patients with moderate to severe Alzheimer's disease.|Treatment of patients with moderate to severe Alzheimer's disease,|Treatment of patients with moderate to severe Alzheimer's disease.,

Memantine is an oral N-methyl-D-aspartate glutamate receptor antagonist used in the therapy of Alzheimer disease and dementia. Memantine is associated with a minimal rate of serum enzyme elevations during therapy and has only rarely been implicated as a cause of clinically apparent acute liver injury.

Alzheimer Disease Agents

Antiparkinson Agents; Dopamine Agents; Excitatory Amino Acid Antagonists|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Memantine is included in the database.|Memantine hydrochloride is used for the palliative treatment of moderate to severe dementia of the Alzheimer's type (Alzheimer's disease). /Included in US product label/|/EXPL THER/ Besides the cognitive impairment and degeneration in the brain, vision dysfunction and retina damage are always prevalent in patients with Alzheimer's disease (AD). The uncompetitive antagonist of the N-methyl-d-aspartate receptor, memantine (MEM), has been proven to improve the cognition of patients with AD. However, limited information exists regarding the mechanism of neurodegeneration and the possible neuroprotective mechanisms of MEM on the retinas of patients with AD. In the present study, by using APPswe/PS1deltaE9 double transgenic (dtg) mice, we found that MEM rescued the loss of retinal ganglion cells (RGCs), as well as improved visual impairments, including improving the P50 component in pattern electroretinograms and the latency delay of the P2 component in flash visual evoked potentials of APPswe/PS1deltaE9 dtg mice. The activated microglia in the retinas of APPswe/PS1deltaE9 dtg mice were also inhibited by MEM. Additionally, the level of glutamine synthetase expressed by Muller cells within the RGC layer was upregulated in APPswe/PS1deltaE9 dtg mice, which was inhibited by MEM. Simultaneously, MEM also reduced the apoptosis of choline acetyl transferase-immunoreactive cholinergic amacrine cells within the RGC layer of AD mice. Moreover, the phosphorylation level of extracellular regulated protein kinases 1 and 2 was increased in APPswe/PS1deltaE9 dtg mice, which was blocked by MEM treatment. These findings suggest that MEM protects RGCs in the retinas of APPswe/PS1deltaE9 dtg mice by modulating the immune response of microglia and the adapted response of Muller cells, making MEM a potential ophthalmic treatment alternative in patients with AD.|For more Therapeutic Uses (Complete) data for MEMANTINE (11 total), please visit the HSDB record page.

FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./|Not known whether memantine is distributed into human milk. However, since many drugs are distributed into human milk, caution is advised if memantine is administered in nursing women.|Mematine has not been systematically evaluated in patients with a seizure disorder. In clinical studies, seizures occurred in 0.2% of patients receiving memantine and in 0.5% of patients receiving placebo.|Safety and efficacy not established in children.|For more Drug Warnings (Complete) data for MEMANTINE (12 total), please visit the HSDB record page.

**General effects** This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate. This leads to the improvement of Alzheimer's dementia symptoms, demonstrated by increased cognition and other beneficial central nervous system effects. **Effects on neuroplasticity** Like other NMDA receptor antagonists, memantine at high doses can reduce neuronal synaptic plasticity that is involved in learning and memory processes. At lower concentrations, which are normally used in the clinical setting, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters. **Effect on various receptors** Memantine has demonstrated minimal activity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, as well as voltage-dependent Ca2+, Na+ or K+ channels. This drug has shown antagonist activity at the 5HT3 receptors. Laboratory studies suggest that memantine does not affect the reversible inhibition of the acetylcholinesterase normally caused by donepezil, galantamine, or tacrine.

Drugs that bind to but do not activate excitatory amino acid receptors, thereby blocking the actions of agonists. (See all compounds classified as Excitatory Amino Acid Antagonists.)|Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists. (See all compounds classified as Antiparkinson Agents.)|Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons. (See all compounds classified as Dopamine Agents.)

After an oral dose, memantine is well absorbed. Its peak drug concentrations are attained in about 3-7 hours. Memantine shows linear pharmacokinetics when given at normal therapeutic doses. This drug can be taken without regard to food, as there is no effect of food on memantine absorption.|This drug is mainly excreted in the urine. Approximately 48% of administered memantine is excreted unchanged in urine. The remainder of the drug is metabolized to three main metabolites. These metabolites are the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine, which show minimal NMDA receptor antagonist activity.|The mean volume of distribution of memantine is 9-11 L/kg.|This drug is cleared by active tubular secretion in the kidneys. Tubular reabsorption of this drug is pH dependent.|Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60-80 hours. The remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.|Following oral administration memantine is highly absorbed with peak concentrations reached in about 3-7 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect on the absorption of memantine.|Memantine hydrochloride is well absorbed following oral administration, with peak plasma concentrations achieved in about 3-7 hours. Memantine is eliminated principally in urine, with approximately 57-82% of an administered dose excreted as unchanged drug; the remainder of the dose is converted to metabolites that exhibit minimal NMDA receptor antagonist activity.|Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 +/- 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation.|For more Absorption, Distribution and Excretion (Complete) data for MEMANTINE (6 total), please visit the HSDB record page.

This drug is partially metabolized in the liver. The hepatic CYP450 enzyme system does not majorly contribute to the metabolism of this drug.|Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.|The hepatic microsomal cytochrome P-450 (CYP) isoenzyme system does not play a substantial role in the metabolism of memantine.

Within the range of 60-100 hours. The terminal elimination half-life was significantly increased in patients with moderate to severe renal impairment, in comparison with patients with normal renal function. Exercise caution when this drug is administered to patients with renal dysfunction.|The terminal elimination half-life of memantine is approximately 60-80 hours.

Continuous activation of the N-methyl-D-aspartate (NMDA) receptors in the central nervous system caused by _glutamate_ is thought to cause some of the Alzheimer's disease symptoms. This overactivation is thought to contribute to neurotoxicity due to the excitatory properties of glutamate. The pharmacological effect of memantine likely occurs via the drug's behavior as an uncompetitive (open-channel) NMDA receptor antagonist, preventing glutamate action on this receptor. Memantine has a preference for the NMDA receptor-operated cation channels. Despite these antagonist effects, memantine has not been proven to prevent or retard the neurodegeneration seen in patients diagnosed with Alzheimer’s disease.|In addition to exhibiting antagonists activity at the NMDA receptor, memantine exhibits antagonist activity at the type 3 serotonergic (5-HT3) receptor with a potency that appears to be similar to that at the NMDA receptor. Memantine also blocks the nicotinic acetylcholine receptor with a potency of about one-sixth to one-tenth that at the NMDA receptor. Memantine exhibits little or no affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.|Memantine is a similar uncompetitive NMDA-receptor antagonist to MK-801 and phencyclidine (PCP), and it prevents nerve cell death induced by the ischemia which induces as excessive release of glutamate. These medicines act on an ion channel binding site similar to the magnesium ion binding site. However, MK-801 and PCP cause schizophrenic symptoms, so they are not being used as a therapeutic drug for Alzheimer's Disease. Memantine does not have those toxicities and does not stimulate acetylcholine release in the cerebral cortex. Although the mechanism of the difference from memantine and MK-801 has not been made clear yet, it seems that memantine is combined and released with the ion channel depending on electric potential in the same way as the magnesium ion.|As an uncompetitive inhibitor of the NMDA receptor, memantine, as with MK-801, does not block the binding of the neurotransmitter ,glutamate, to the receptor but rather blocks the ion current through the receptor channel that is activated by glutamate. ... Unlike such high affinity antagonist (MK-80), memantine blocks the NMDA receptor with relatively strong voltage dependence and rapid blocking/unblocking kinetics, dissociating from the NMDA receptors in response to membrane depolarization more readily than MK-801. ... Memantine is able to dissociate from the receptor in response to the strong, transient depolarizations that trigger physiological NMDA receptor activity, while blocking the receptor channels during the chronic, low level excitation that is thought to occur in neurodegenerative diseases such as Alzheimer's disease.|Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor, but the key binding interactions between drug and receptor are not fully elucidated. To determine key binding interactions of memantine, we made side-by-side comparisons of IC(50) for memantine and amantadine, a structurally related drug, in the GluN1/GluN2B NMDA receptor. We identified hydrophobic binding pockets for the two methyl groups on memantine formed by the residues A645 and A644 on the third transmembrane helices of GluN1 and GluN2B, respectively. Moreover, we found that while adding two methyl groups to amantadine to produce memantine greatly improves affinity, adding a third methyl group to produce the symmetrical trimethylamantadine diminished affinity. Our results provide a better understanding of chemical-scale interactions between memantine and the NMDA channel, which will potentially benefit the development of new drugs for neurodegenerative diseases involving NMDA receptors.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ The authors retrospectively reviewed the clinical records of 196 patients with dementia treated with memantine for at least 6 months. Eleven (5.6%) developed treatment-induced agitation. At chi-square analysis, they were significantly more likely to have a history of similar side effects from other medications acting on the central nervous system in comparison with the group without agitation, suggesting neurochemical susceptibility. A trend toward a significantly greater prevalence was also present for ischemic cardiopathy and neuroimaging evidence of chronic small vessel disease. Ischemic brain and heart disease might contribute through anatomical and functional alterations within the glutamatergic system.|/HUMAN EXPOSURE STUDIES/ Abstract AIM: Memantine hydrochloride (Memary), launched in June 2011 in Japan, is used in patients with moderate to severe Alzheimer's disease. We performed an integrated analysis of data obtained from different clinical studies of memantine hydrochloride conducted between 2002 and 2011 in Japan in order to examine the long-term tolerability and efficacy of this drug at a dose of 20 mg/day. METHODS: Using clinical studies of memantine hydrochloride performed in Japan between 2002 and 2011, the therapeutic safety and the time course of MMSE scores in 702 subjects who had received memantine hydrochloride were examined. RESULTS: The mean duration of memantine treatment was 798.1 days, with the longest duration of 3,373 days (approximately nine years and two months). The incidence of adverse events every 52 weeks of treatment ranged from 71.0% to 88.9%, and the incidence of adverse drug reactions ranged from 5.6% to 32.1%, with no associations between the incidence of adverse events and the treatment duration. There were no adverse drug reactions specific to the long-term administration of this drug. The occurrence of "adverse events" was the primary reason for drug discontinuation. During the long-term study observation period, there were many cases of adverse events and treatment discontinuation due to the background factors of the subjects, including adverse events associated with aging and progression of the underlying conditions. In addition, treatment discontinuation was also associated with admission to a nursing home or facility due to changes in home nursing care. The degree of MMSE score reduction over time was lower in the patients treated with memantine than the expected MMSE score reduction observed in the untreated patients. CONCLUSIONS: Based on these findings, there are no issues regarding the tolerability of memantine hydrochloride administered at a dose of 20 mg/day over the long term. Considering changes in the MMSE score, the results indicated that memantine hydrochloride may inhibit worsening of the cognitive function for long periods of time in patients with Alzheimer's disease.|/HUMAN EXPOSURE STUDIES/ Abstract OBJECTIVE: Enhanced N-methyl-D-aspartate (NMDA) receptor function associated with a positive family history of alcoholism (FHP) has been hypothesized to contribute to the heritable risk for alcoholism. The objective of this study was to evaluate the relationship of alcoholism family history, NMDA receptor function, and cortical information processing by testing acute effects of the NMDA receptor antagonist memantine on event-related potential (ERP). METHOD: Twenty-two healthy FHP and 20 healthy family history-negative (FHN; no alcoholic relatives) subjects were administered placebo or 40 mg of memantine under double-blind counterbalanced conditions on two separate occasions. Electroencephalogram data were collected from eight channels with eyes open during an auditory oddball discrimination task. We evaluated P3b amplitude, total theta, alpha activity, and fractal dimension from ERP trials. RESULTS: FHP and FHN subjects did not differ in P3b amplitude. A significant Group x Drug interaction was observed in theta, alpha activity, and fractal dimension at the parietal and occipital sites. FHP individuals exhibited significantly higher fractal dimension and lower theta and alpha activity after placebo relative to FHN subjects. Following memantine administration, theta activity decreased in both groups but more markedly for FHN individuals. Alpha activity decreased for FHN subjects and increased for FHP individuals, whereas the fractal dimension decreased for FHP subjects and increased for FHN subjects after memantine. CONCLUSIONS: A plausible interpretation of these results is that FHP individuals may have altered NMDA receptor function compared with FHN individuals. These findings provide additional evidence of differences in the regulation of NMDA receptor function between FHP and FHN individuals.|/SIGNS AND SYMPTOMS/ Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness.|For more Human Toxicity Excerpts (Complete) data for MEMANTINE (8 total), please visit the HSDB record page.

1,3-Dimethyl-5-aminoadamantane

Table: Memantine Hydrochloride Preparations [Table#6926]

NMDA-receptor antagonist; derivative of adamantane.|Information available in 2005 indicated that Memantine hydrochloride was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Colombia, Denmark, Dominican Republic, El Salvador, Finland, France, Germany, Guatemala, Honduras, Hungary, Ireland, Luxembourg, Norway, Panama, Russian Federation, Spain, Switzerland, United Kingdom, United States (1,2)

Memantine is chemically a tricyclic amine and is used for Parkinson's disease and movement disorders. Although several HPLC methods with different derivatization reagents have been developed for the determination of memantine in biological fluids, there are some complications which limit the use of these methods in routine analysis of memantine in in vitro tests. We established a simple, sensitive, precise, and accurate HPLC method for the quantification of memantine in dosage forms. Pre-column derivatization of memantine was performed with 1-fluoro-2,4-dinitrobenzene and the reaction product was separated on a Nova-Pak C18 column. A mixture of acetonitrile and sodium dihydrogenphosphate (pH 2.5; 0.05 M) (70: 30, v/v) was used as the mobile phase. UV detection was performed at 360 nm. Forced degradation studies were performed on a powdered tablet sample of memantine hydro-chloride using acidic (0.1 M hydrochloric acid), basic (0.1 M sodium hydroxide), oxidative (10% hydrogen peroxide), thermal (105 °C), photolytic, and humidity conditions. Good linearity (r(2)=0.999) was obtained over the range of 1-12 ug mL(-1) of memantine hydrochloride with acceptable within-day and between-day precision values in the range of 0.05-0.95%. The proposed method was used for the assay determination and dissolution rate study of memantine dosage forms with excellent specificity.|A modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) method using multi-walled carbon nanotubes (MWCNTs) as a reversed-dispersive solid phase extraction (r-dSPE) material combined with ultra-high liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was developed for the simultaneous determination of amantadine, rimantadine and memantine in chicken muscle. The satisfactory separation of isomers (rimantadine and memantine) was obtained on an Acquity BEH C18 column (2.1 mm x 100 mm, 1.7 um) after optimization of mobile phase composition, column temperature and flow rate. The method involved an acetonitrile-based sample preparation and a dSPE clean-up procedure with MWCNTs material. Variations in the type and amount of MWCNTs, the pH value of the extract, the extraction time for MWCNTs, and the type of eluent were used to determine the optimal parameters for increasing the sample throughput and the sensitivity. The samples were quantified using amantadine-D15, rimantadine-D4 and memantine-D6 as the internal standards. Under the optimized conditions, recoveries of 96.8-104.6% and the values of coefficient of variation (CV) of 3.8-6.4% were obtained for the three drugs in chicken muscle at three spiked levels (0.5, 1.0 and 1.5 ug/kg), and the decision limits (CCa) and detection capabilities (CCbeta) were 0.15-0.20 ug/kg and 0.20-0.25 ug/kg, respectively. Positive results were obtained from local supermarket using this method, and the concentrations obtained from the newly developed method compared well to the previously reported method.

A novel, simple, and sensitive method based on the use of dispersive micro-solid-phase extraction (d-u-SPE) procedure combined with ultra-fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS) for the determination of memantine (ME) was developed and validated over the linearity range 0.05-10.0 ug/L with 100 uL of human plasma using memantine-D6 (ME-D6) as the internal standard. The novel nanoring carboxyl-functionalized paramagnetic molecularly imprinted polymer (NR-CF-Mag-MIP) was synthesized by ultrasound-assisted suspension polymerization, using ME as a template molecule, methacrylic acid as a functional monomer, and divinylbenzene as a cross-linking agent. The NR-CF-Mag-MIP was used as the d-u-SPE sorbent to extract ME from human plasma samples. The obtained results demonstrated the higher extraction capacity of NR-CF-Mag-MIP with recoveries between 97.6 and 101%. The limits of quantification (LOQs) for ME was 0.015 ug/L. Validation results on linearity, specificity, accuracy, precision, and stability, as well as on application to the analysis of samples taken up to 480 hr after oral administration of 20 mg (two 10 mg capsules) of ME in healthy volunteers demonstrated the applicability to bioequivalence studies.|HPLC determination in plasma.

Human drugs -> Axura -> EMA Drug Category|Other anti-dementia drugs -> Human pharmacotherapeutic group|Human drugs -> Memantine Mylan -> EMA Drug Category|Other anti-dementia drugs, Psychoanaleptics -> Human pharmacotherapeutic group|Human drugs -> Memantine Accord -> EMA Drug Category|Human drugs -> Ebixa -> EMA Drug Category|Human drugs -> Nemdatine -> EMA Drug Category|Psychoanaleptics, Other anti-dementia drugs -> Human pharmacotherapeutic group|Human drugs -> Memantine ratiopharm -> EMA Drug Category|Psychoanaleptics -> Human pharmacotherapeutic group|Human drugs -> Marixino (previously Maruxa) -> EMA Drug Category|Human drugs -> Memantine LEK -> EMA Drug Category|Pharmaceuticals