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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