Memantine

Absorption

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 .

Toxicity

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 .

Description

Memantine is a potent antagonist of the N-methyl-D-aspartate (NMDA) receptor. Experimentally, memantine inhibits and reverses the abnor-mal activity of a protein phosphatase (PP-2A) that leads to tauhyperphosphorylation and to neurofibrillary degeneration inAD. Memantine is effective and well toler-ated in patients with severe AD and wasapproved by the FDA for the treatment of moderate-to-severe AD.

Originator

Akatinol,Merz,W. Germany,1983

The Uses of Memantine

Recent phase 3 clinical trials have shown that Memantine is an effective way of treatment of both mild and moderate-to-severe Alzheimer''s disease and possibly vascular dementia (multi-infarct dementia). Memantine’s method of action involves an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission.

The Uses of Memantine

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Background

Initially approved by the FDA in 2013, memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist used in the management of Alzheimer's Disease (AD). It is different from many other Alzheimer's Disease medications, as it works by a different mechanism than the cholinesterase enzyme inhibitors normally employed in the management of Alzheimer's disease . Memantine blocks the effects of glutamate, a neurotransmitter in the brain that leads to neuronal excitability and excessive stimulation in Alzheimer's Disease .
In 2010, it was estimated that 36 million people worldwide live with Alzheimer's Disease. In 2013, this number increased to 44 million. Almost doubling every 20 years, the prevalence of Alzheimer's Disease is predicted to reach 66 million by 2030 and to 115 million by 2050 . In December 2013, the G8 dementia summit concluded that dementia should be considered a global priority with the objective of developing a cure or a disease-modifying therapy by the year 2025 .

Indications

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 .

Definition

ChEBI: A primary aliphatic amine that is the 3,5-dimethyl derivative of 1-aminoadamantane. A low to moderate affinity uncompetitive (open-channel); NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels.

What are the applications of Application

Memantine has been used in patients with VaD basedon its experimental efficacy in animal models of ischaemiclesions.Memantine acts on potentially contributing factorssuch as neuronal depolarization，mitochondrial dysfunc-tion, magnesium effects on NMDA receptors and chronicglutamatergic overstimulation; it also has shown positiveeffects on long-term potentiation and cognitive tests in stan-dard animal models of impaired synaptic plasticity.

Manufacturing Process

A mixture of 24 g of 1,3-dimethyladamantane and 80 ml of bromine was refluxed for 6 hours. The reaction product mixture was cooled, taken up in about 200 ml of chloroform, and poured onto ice. The excess bromine was removed by adding sodium hydrosulfite. The chloroform layer was separated from the aqueous layer, dried, concentrated in vacuo, and distilled at reduced pressure to yield 30.5 g of product having a boiling point of about 118°C at 5- 6 mm; nD25 = 1.5169-1.5182. The product was identified by nuclear magnetic resonance (NMR) and elemental analyses as 1-bromo-3,5- dimethyladamantane.
A mixture of 20 g of 1-bromo-3,5-dimethyladamantane, 75 ml of acetonitrile, and 150 ml of concentrated sulfuric acid was allowed to react overnight at ambient room temperature. The red reaction product mixture was poured over crushed ice, and the white solid which precipitated was taken up in benzene and the benzene solution dried over sodium hydroxide pellets. The benzene solution was filtered from the drying agent and evaporated to dryness in vacuo to yield 18.2 g of product having a melting point of about 97°C and identified by infrared spectrum as 1-scetamido-3,5-dimethyladamantane.
A mixture of 18 g of 1-acetamido-3,5-dimethyladamantane, 38 g of sodium hydroxide, and 300 ml of diethylene glycol was refluxed for a period of 6 hours. The reaction product mixture was cooled and poured onto about 2,000 ml of crushed ice. The basic solution thus obtained was extracted five times with 250 ml portions of benzene and the aqueous layer was discarded. The combined benzene extracts were dried over sodium hydroxide and the dried benzene solution concentrated in vacuo to give a crude oil weighing 14 g and having nD25 = 1.4941, A 4 g sample of the crude oil was dissolved in ether and the solution saturated with anhydrous hydrogen chloride. The solid which precipitated was filtered off and recrystallized from a mixture of alcohol and ether to yield product weighing 3.5 g and melting at 258°C.
It was identified by analysis as 1-amino-3,5-dimethyladamantane hydrochloride.

Therapeutic Function

Spasmolytic

Biological Activity

An antagonist at the NMDA receptor, binding to the ion channel site. Used in the treatment of Parkinsonism.

Pharmacokinetics

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 .

Clinical Use

NMDA-receptor antagonist:
Treatment of moderate to severe dementia in Alzheimer’s disease

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: increased risk of CNS toxicity with ketamine – avoid.
Analgesics: increased risk of CNS toxicity with dextromethorphan – avoid.
Dopaminergics: possibly enhances effects of dopaminergics and selegiline; increased risk of CNS toxicity with amantadine – avoid.

Metabolism

This drug is partially metabolized in the liver. The hepatic CYP450 enzyme system does not majorly contribute to the metabolism of this drug .

Metabolism

Memantine undergoes partial hepatic metabolism to form mainly three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitrosodeaminated memantine. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.