Memantine

ByBy

Sirinoot JantharangkulSirinoot Jantharangkul

Memantine

BySirinoot Jantharangkul

MMemantine emantine Brand name :Brand name : NAMENDA NAMENDA

US FDA Approval :October 2003US FDA Approval :October 2003

NMDA (N-methyl-D-aspartate) receptor NMDA (N-methyl-D-aspartate) receptor antagonistantagonist

IIndicated for the treatment of moderate to ndicated for the treatment of moderate to

severe severe Alzheimer’s DiseaseAlzheimer’s Disease

Alzheimer’s DiseaseAlzheimer’s Disease

Degenerative disease of Degenerative disease of the brainthe brain

Prevalence : 50% in those Prevalence : 50% in those > 85 years> 85 years

More common in womenMore common in women

Average life span is 8-10 Average life span is 8-10 years after diagnosisyears after diagnosis

Cause of death: aspiration, infection, malnutrition

Alzheimer’s DiseaseAlzheimer’s Disease

CauseCause1.1. Genetic factorGenetic factor : : Early onset and Late onsetEarly onset and Late onset

Early onsetEarly onset : <65years : <65years

- Amyloid precursor protein (APP)- Amyloid precursor protein (APP) on on

chromosome 21, chromosome 14 chromosome 21, chromosome 14

and chromosome 1and chromosome 1

Amyloid precursor protein (APP)Amyloid precursor protein (APP)

Amyloid Amyloid ββ- protein- protein

Alzheimer’s DiseaseAlzheimer’s Disease

Late onsetLate onset : >65years : >65years

- Apolipoprotein E4(Apo E4) on - Apolipoprotein E4(Apo E4) on

chromosome19chromosome19

2.Nongenetic factor2.Nongenetic factor - - Inflammatory mediatorsInflammatory mediators

- Neurochemical- Neurochemical: reduction in choline : reduction in choline

acetyltransferaseacetyltransferase

- Heavy metal toxicity- Heavy metal toxicity : aluminium toxicity : aluminium toxicity

PathophysiologyPathophysiology

Two hallmake histopathology featuresTwo hallmake histopathology featuresNeuriticNeuritic plaques plaques

small spheres containing small spheres containing ββ-amyloid-amyloid

NeurofibrillaryNeurofibrillary tangle tangle Abnormal neuron containing bundles ofAbnormal neuron containing bundles of

paired helical filamentous structure woundpaired helical filamentous structure wound around each other in the cytoplasmaround each other in the cytoplasm

40-90%reduction in choline 40-90%reduction in choline acetyltransferaseacetyltransferase

Cholinergic HypothesisCholinergic Hypothesis

Role:Role: Acetycholine is an important Acetycholine is an important neurotransmitter in brain regions neurotransmitter in brain regions involved in memoryinvolved in memoryLoss of ACh in AD correlates with Loss of ACh in AD correlates with impairment of memoryimpairment of memoryTreatment approach:Treatment approach: Enhancement of Enhancement of cholinergic function may stabilize or cholinergic function may stabilize or improve cognitive function and affect improve cognitive function and affect behavior and daily functioning behavior and daily functioning

Acytylcholinesterase inhibitorsAcytylcholinesterase inhibitors– TacrineTacrine– DonepezilDonepezil– RivastigmineRivastigmine– GalantamineGalantamine

IIndicated for the treatment of ndicated for the treatment of mind to mind to

moderate moderate Alzheimer’s DiseaseAlzheimer’s Disease

Glutamatergic HypothesisGlutamatergic Hypothesis

GlutamatergicGlutamatergic is a major excitatory is a major excitatory neurotransmitter in the cortex and neurotransmitter in the cortex and hippocampushippocampus

Essential for learning and memory Essential for learning and memory processesprocesses

NMDA type glutamate receptors mayNMDA type glutamate receptors may be be over activated in AD ( glutamatergic over activated in AD ( glutamatergic excitotoxicity)excitotoxicity)

Glutamatergic excitotoxicityGlutamatergic excitotoxicity

NMDA receptor antagonistNMDA receptor antagonist– MemantineMemantineIIndicated for the treatment of moderate to ndicated for the treatment of moderate to

severe severe Alzheimer’s DiseaseAlzheimer’s Disease

Memantine

MemantineStructural formula:

� For oral administration as

capsule-shaped, film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride

Molecular weight :215.76

Mechanism of action

Mechanism of action

Mechanism of action

Pharmacokinetics� Absorption

– Bioavailability of approximately 100%

– Food has no effect on the absorption of memantine.

– T max : 3-7 hours� Distribution

– Vd : 9-11 l/kg– Protein binding : low(45%)

Pharmacokinetics� Metabolism and Elimination

– little metabolism – the majority of an administered dose

eliminated as the parent drug via •the kidneys :75% to 90%•the feces : 10 %to 25%

– A small amount of the drug is converted to three polar metabolites•N-glucuronide•6-hydroxy memantine•1-nitroso-deaminated memantine

– terminal elimination half-life of approximately 60 to 80 hours

Drug interactions� NMDA antagonists

– amantadine, ketamine, and dextromethorphan

� Renal tubular secretion– HCTZ,cimetidine and ranitidine

ect.� Urine alkalinzers

– Carbonic anhydrase inhibitor,sodium bicarbonate

Contraindications� Hypersensitivity to

memantine or any

components of the memantine formulation.

Adverse events–Dizziness–Headache–Somnolence

–Hypertension

–Constipation

–Vomiting –Back pain –Fatigue

Precaution� Special Populations

– Hepatic Impairment: have not been investigated, but would be expected to be only modestly affected.

– Renal Impairment:No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment

� Carcinogenesis– There was no evidence of

carcinogenicity in a 113-week oral study in mice

Precaution� Impairment of Fertility

– No impairment of fertility or reproductive performance was seen in rats

� Pregnancy– Category B: Memantine given orally

to pregnant rats and pregnant rabbits during the period of

organogenesis was not teratogenic up

� Nursing Mothers:– It is not known whether memantine

is excreted in human breast milk. caution should be exercised when memantine is administered to a nursing mother

Dosage and administration� The recommended target dose is

20 mg/day. � The recommended starting dose

is 5 mg once daily.� The minimum recommended

interval between dose increases

is one week.– should be increased in 5 mg

increments to 10 mg/day (5 mg twice a day)

– 15 mg/day (5 mg and 10 mg as separate doses)

– 20 mg/day (10 mg twice a day)

Clinical studies

Memantine in Moderate-to-SevereAlzheimer’s Disease

Barry Reisberg, M.D., Rachelle Doody, M.D., Ph.D., Albrecht

Stoffler, M.D.,Frederick Schmitt, Ph.D.,

Steven Ferris, Ph.D.,and Hans Jorg Mobius, M.D.,

Ph.D., for the Memantine Study Group*

The new England journal of medicine, 2003

Patients and methods� double-blind randomized 2-arm multi-

center study� Patients

– 252 out-patients– required the patients to be over the

age of 50– diagnosed with Alzheimer’s disease

(DSM-IV)– MMSE(Mini-Mental State Examination)

scores: 3 to 14– GDS(Global Deterioration Scale): stage 5

or 6� randomized to receive either 20 mg

memantine daily or placebo for 28 weeks.

Patients and methods� Efficacy variables

– CIBIC-Plus (Clinician’s Interview-Based Impression of Change Plus Caregiver Input)

– ADCS-ADL (Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory)

– Severe Impairment Battery– FAST(The Functional Assessment

Staging scale)

� Measures of safety– physical examinations;vital signs,

electrocardiography– laboratory tests (hematologic tests,

blood chemical values, and urinalysis)– recording of adverse events.

Results

Results

Results

Conclusions� Memantine reduced clinical

deterioration– Activities of daily living– Cognitive performance

in moderate-to-severe Alzheimer’s disease, a phase associated with distress for patients and burden on caregivers

Rivastigmine monotherapy and combination therapy with

memantine in patients with moderately severe Alzheimer’s

disease who failed to benefit from previous cholinesterase

inhibitor treatmentT. DANTOINE, S. AURIACOMBE,M. SARAZIN, H. BECKER,4 J-J PERE, I .

BOURDEIX

2006 Blackwell Publishing Ltd Int J Clin Pract, January 2006, 60, 1, 1

10–118

Patients and methods� Patients

– male and female ,202 out patients– least 50 years of age– AD according to the Diagnostic and

Statistical Manual of Mental Disorders-IV (DSM-

IV) criteria– Mini-Mental State Examination (MMSE)

scores of <18– Global Deterioration Scale (GDS) scores

of > 4

Patients and methods� Study disign: Prospective,

multicenter, open-label study that comprised two phases,switched from either donepezil or galantaminerivastigmine treatment phase (3-16mg/day)rivastigmine treatment phase (3-16mg/day)

rivastigmine+memantine 5-20mg/dayrivastigmine+memantine 5-20mg/day

MMSE score ≥ baselineMMSE score < baseline

completed

Ph.1

16wksPh.2

12wks

Patients and methods� Outcome Measures

–Efficacy•Primary end point: MMSE•Secondary end point:

–Mini-Zarit Inventory (Burden of Caregiver)

–Neuropsychiatric Inventory (NPI) –Ten-point Clock-drawing test–Delis–Kaplan Executive Function

System (D-KEFS) verbal fluency test

– Safety: vital signs, adverse events, physical examination

Conclusions� When patients fail on donepezil

or galantamine,switching to

rivastigmine may improve cognition and behaviour

� Should they continue to deteriorate, the addition of

memantine may be beneficial.

Conclusions� NMDA receptor antagonist� US FDA approved for

moderate to severe AD� Recommended dose of 20

mg /day� Can be used concomitantly

with AChEI� Good safety and tolerability

profiles

จบแล้ว......ขอบคณุคร ับ

Acytylcholinesterase inhibitorsAcytylcholinesterase inhibitors

Neurofibrillary tangleNeurofibrillary tangleTau proteinTau protein

Deposit intraneuronalDeposit intraneuronal

KinaseKinase PhosphatasePhosphatase

Neuronal deathNeuronal death

Hyperphosphorylated tau proteinHyperphosphorylated tau protein

Paired helical filaments (PHFs) tauPaired helical filaments (PHFs) tau

Disrupt microtubulesDisrupt microtubules

Loss of synapse & neuronal dysfunctionLoss of synapse & neuronal dysfunction

Glutamatergic excitotoxicityGlutamatergic excitotoxicityIncreased glutamate level

activation of NMDA receptors

Cognitive deficit from decreased signal:noise

Neuronal death from prolonged Ca 2+ influx

Symptoms and Symptoms and Progression

Progression: Early– Memory loss (short term)– Unable to lay down new memory– Increased need for lists– Difficulty managing money– Anomia

Symptoms and Symptoms and Progression

Progression: Moderate– Unable to use objects/execute complex

movements but no impairment in muscles /senses (apraxia)– Unable to draw complex figures or conceptualize orientation in space (constructional apraxia)– Unable to perform routine household tasks

Symptoms and Symptoms and Progression

Progression: Severe– Become lost in own home– Unable to recognize family/friends– Unable to speak (aphasia)– Judgment extremely impaired– Final stages: unable to eat, walk / communicate

Mechanism of action� low to moderate affinity

uncompetitive NMDA receptor antagonist

� preferentially to the NMDA receptor-operated cation channels

� low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels

� blocked nicotinic acetylcholine receptors

Results

The NMDA Receptor