Presented by

Kirmal Masih

Medicinal Chemistry

March 25th

Alzheimer's disease (AD), also known asSenile Dementia of the Alzheimer Type(SDAT) or simply Alzheimer’s is the mostcommon form of dementia.

This incurable, degenerative, terminaldisease was first described by a Germanpsychiatrist and neuropathologist AloisAlzheimer in 1906 and was named afterhim.

Alzheimer's disease (AD) is a slowlyprogressive disease of the brain that ischaracterized by impairment ofmemory and eventually bydisturbances in reasoning, planning,language, and perception.

Many scientists believe thatAlzheimer's disease results from anincrease in the production oraccumulation of a specific protein (β-amyloid protein) in the brain that leadsto nerve cell death.

• Generally, it is diagnosed in people over65 years of age, although the less-prevalent early onset of Alzheimer’s canoccur much earlier.

• In 2006, there were 26.6 millionsufferers worldwide.

• Alzheimer’s is predicted to affect 1 in 85people globally by 2050.

1) Early StageThis is considered as a mild/early stage and

the duration period is 2-4 years.Frequent recent memory loss, particularly

of recent conversations and events.Repeated questions, some problems

expressing and understanding language.Writing and using objects become difficult

and depression and apathy can occur.Drastic personality changes may accompany

functional decline.Need reminders for daily activities and

difficulties with sequencing impact drivingearly in this stage.

2) Second stageThis is considered as a middle/moderate stage and

the duration is 2-10 years.Can no longer cover up problems.Pervasive and persistent memory loss impacts life

across settings.Rambling speech, unusual reasoning, confusion

about current events, time, and place.Potential to become lost in familiar settings, sleep

disturbances, and mood or behavioral symptomsaccelerate.

Nearly 80% of patients exhibit emotional andbehavioral problems which are aggravated bystress and change.

Slowness, rigidity, tremors, and gait problemsimpact mobility and coordination.

Need structure, reminders, and assistance withactivities of daily living.

3) Moderate stage

Increased memory loss and confusion.

Problems recognizing family and friends.

Inability to learn new things.

Difficulty carrying out tasks that involvemultiple steps (such as getting dressed).

Problems coping with new situations.

Delusions and paranoia.

Impulsive behavior.

In moderate AD, damage occurs in areas ofthe brain that control language, reasoning,sensory processing, and conscious thought

4) Last stage

This is considered as the severe stage andthe duration is 1-3 years.

Confused about past and present. Loss ofrecognition of familiar people and places

Generally incapacitated with severe to totalloss of verbal skills.

Unable to care for self. Falls possible andimmobility likely.

Problems with swallowing, incontinence, andillness.

Extreme problems with mood, behavioralproblems, hallucinations, and delirium.

Patients need total support and care, andoften die from infections or pneumonia

Alzheimer's disease is usually diagnosedclinically from the patient history,collateral history from relatives, andclinical observations, based on thepresence of characteristic neurologicaland neuropsychological features and theabsence of alternative conditions.

Advanced medical imaging withcomputed tomography (CT) or magneticresonance imaging (MRI), and with singlephoton emission computer tomography(SPECT) or positron emissiontomography (PET) can be used to helpexclude other cerebral pathology orsubtypes of dementia.

The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.

.

PET scan of the brain of a person with AD showing a loss of function in the temporal lobe.

Neuropsychological tests such as themini-mental state examination (MMSE)are widely used to evaluate the cognitiveimpairments needed for diagnosis. Morecomprehensive test arrays are necessaryfor high reliability of results, particularlyin the earliest stages of the disease.

Psychological tests for depression areemployed, since depression can eitherbe concurrent with AD, an early sign ofcognitive impairment, or even the cause.

• When available as a diagnostic tool,SPECT and PET neuroimaging are used toconfirm a diagnosis of Alzheimer's inconjunction with evaluations involvingmental status examination. In a personalready having dementia, SPECT appearsto be superior in differentiatingAlzheimer's disease from other possiblecauses, compared with the usualattempts employing mental testing andmedical history analysis.

Scientists don’t yet fully understandwhat causes AD, but it is clear that itdevelops because of a complex seriesof events that take place in the brainover a long period of time. It is likelythat the causes include genetic,environmental, and lifestyle factors.

Some drug therapies propose that ADis caused by reduced synthesis of theneurotransmitter acetylcholine.

Other cholinergic effects have alsobeen proposed, for example, initiationof large-scale aggregation of amyloidleading to generalizedneuroinflammation.

• Alzheimer's disease is characterized by abuild-up of proteins in the brain. Thoughthis cannot be measured in a livingperson, extensive autopsy studies haverevealed this phenomenon. The build-upmanifests in two ways:

Plaques– deposits of the protein β-amyloid that accumulate in the spacesbetween nerve cells

Tangles – deposits of the protein tauthat accumulate inside of nerve cells

Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein.

Alzheimer's disease is characterised by loss of neurons andsynapses in the cerebral cortex and certain subcorticalregions. This loss results in gross atrophy of the affectedregions, including degeneration in the temporal lobe andparietal lobe, and parts of the frontal cortex and cingulategyrus.

Both amyloid plaques and neurofibrillarytangles are clearly visible by microscopyin brains of those afflicted by AD.

Plaques are dense, mostly insolubledeposits of amyloid – β peptides andcellular material outside and aroundneurons.

Tangles (neurofibrillary tangles) areaggregates of the microtubule-associatedprotein tau which has becomehyperphosphorylated and accumulateinside the cells themselves.

Although many older individuals developsome plaques and tangles as aconsequence of ageing, the brains of ADpatients have a greater number of themin specific brain regions such as thetemporal lobe.

Alzheimer's disease has been identified asa protein misfolding disease (proteopathy),caused by accumulation of abnormallyfolded A-β and tau proteins in the brain.Plaques are made up of small peptides, 39–43 amino acids in length, called 𝜷-amyloid(also written as A-β or Aβ).

β-amyloid is a fragment from a largerprotein called amyloid precursor protein(APP), a transmembrane protein thatpenetrates through the neuron'smembrane.

• APP is critical to neuron growth, survivaland post-injury repair. In Alzheimer'sdisease, an unknown process causesAPP to be divided into smaller fragmentsby enzymes through proteolysis.

• One of these fragments gives rise tofibrils of β-amyloid, which form clumpsthat deposit outside neurons in denseformations known as senile plaques

AD is also considered a tauopathy due toabnormal aggregation of the tau protein.Every neuron has a cytoskeleton, aninternal support structure partly madeup of structures called microtubules.

These microtubules act like tracks,guiding nutrients and molecules fromthe body of the cell to the ends of theaxon and back. A protein called taustabilizes the microtubules whenphosphorylated, and is therefore called amicrotubule-associated protein.

• In AD, tau undergoes chemical changes,becoming hyperphosphorylated; it thenbegins to pair with other threads,creating neurofibrillary tangles anddisintegrating the neuron's transportsystem.

Exactly how disturbances of production and aggregation ofthe β amyloid peptide gives rise to the pathology of AD isnot known.

The amyloid hypothesis traditionally points to theaccumulation of β- amyloid peptides as the central eventtriggering neuron degeneration.

Accumulation of aggregated amyloid fibrils, which arebelieved to be the toxic form of the protein responsible fordisrupting the cell's calcium ion homeostasis, inducesprogrammed cell death (apoptosis).

It is also known that A β selectively builds up in themitochondria in the cells of Alzheimer's-affected brains,and it also inhibits certain enzyme functions and theutilization of glucose by neurons.

Various inflammatory processes and cytokines may alsohave a role in the pathology of Alzheimer's disease.Inflammation is a general marker of tissue damage in anydisease, and may be either secondary to tissue damage inAD or a marker of an immunological response

Alterations in the distribution of different neurotrophicfactors and in the expression of their receptors such as thebrain derived neurotrophic factor (BDNF) have beendescribed in AD

• Apolipoprotein E (APOE) found on chromosome 19appears to be a predisposing genetic risk factor for thelate onset of AD – the most typical AD.

• APOE helps carry cholesterol in the bloodstream.

• APOE comes in several different forms, or alleles.

• Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.

Treatment for Alzheimer’s Disease

Treatment Goal

• Currently there is no current therapy to treatAlzheimer’s disease. Current therapy isaimed at prolonging the patient’s cognitivefunction and secondary goals includesymptomatically treating psychiatric andbehavioral abnormalities

• Current therapy has not been shown toprolong life, cure AD, halt or reverse thepathophysiological degradation of thedisease

Natural Disease Progression

• Alzheimer’s Disease Assessment Scale-Cognition (ADAS-cog) scores worsen by anaverage of 4 points over 6 months and 7points over 1 year

• 4 points represents a clinically significantchange

• In clinical practice a Mini Mental StatusExamination (MMSE) is used due to timerequirements of the ADAS-cog– An untreated patient has an average decline of

2-4 points per year

Brain Comparison

Ideal Treatment

• Improving symptomatic decline byimproving cognitive function, dailyactivities, and behavior

– Current therapy

• Arrests the neurodegenerative molecularprocess

– Research needed

Treatment Algorithm

• Cholinesterase Inhibitor

• NMDA Antagonist

• Cholinesterase Inhibitor + NMDAantagonist

• Titrate doses to recommendedmaintenance therapy as tolerated

• Symptomatic approach is used to treatbehavioral symptoms

Cholinesterase Inhibitors

Cholinesterase Inhibitors• Donepezil (Aricept)- used in mild to severe

disease

• Galantamine (Razadyne)- used in mild tomoderate disease

• Rivastigmine (Exelon)- used in mild tomoderate disease

• Combination of more than one cholinesteraseinhibitor is not recommended

• Choice of therapy often selected based on easeof use for the patient, cost and safety issues

• Switching can occur if patients are nottolerating the initial treatment or a treatmentfailure

– If MMSE decline is greater than 2-4 points inone year changing therapy is warranted

Cholinesterase Inhibitors• Donepezil, Rivastigmine and Galantamine

• All show similar efficacy and adverse eventprofiles with gastrointestinal complaintsbeing the most common symptom

• Dose titration over several months can helptolerability of urinary incontinence,dizziness, headache, syncope, bradycardia,muscle weakness, salivation and sweating

• Abrupt discontinuation is discouraged dueto worsening of cognition or behavioralproblems in some medications

• Avoid use with anti-cholinergic medicationswhich is especially important when trying totreat behavioral abnormalities.

Cholinesterase Inhibitors Mechanism of Action

• Donepezil- specifically and reversibly inhibitsacetylcholinesterase

• Rivastigmine- inhibits bothbutylcholinesterase and acetylcholinesterase

• Galantamine- selective, competitive,reversible acetylcholinesterasse inhibitorand also enhances the action ofacetylcholine on nicotinic receptors

• Clinical relevance is unknown

NMDA Antagonist

N-methyl-D Aspartate (NMDA) Antagonist

• Memantine- used in moderate to severedisease

– Not recommended in early stages of thedisease

– Only NMDA-antagonist available

– Blocks glutamatergic neurotransmission byantagonizing NMDA receptors

• Glutamate an excitatoryneurotransmitter in the brain

– Most common side effects includeconstipation, confusion, dizziness,headache, hallucinations, coughing, andhypertension

Dosage Forms

• Galantamine (Razadyne)- capsule, tablet, and solution

• Donepezil (Aricept)- tablet (oral disintegrating tablet)

• Rivastigmine (Exelon)- capsule, patch, and solution

• Memantine (Namenda)- tablet and solution

Treatment for Non-cognitive Symptoms

• Psychosis

• Disruptive behavior

• Depression

• Environmental interventions then pharmacological therapy

• Limited clinical data; therefore, treatment is empirical

• General guidelines: reduced doses, close monitoring closely, slow dose titrations, and careful documentation

• Cholinesterase inhibitors and memantine should be considered as first line therapy in patients with behavior abnormalities in the beginning stages of AD

Antipsychotics

• Haloperidol• Olanzapine• Quetiapine• Risperidone• Ziprasidone• Treatment of psychosis: hallucinations,

delusions, suspicions• Treatment of disruptive behaviors: Agitation

and aggression• Not FDA approved

Concern with Antipsychotics

• Worsening cognitive impairment, oversedation, falls, tardive dyskinesia, neuroleptic malignant syndrome, hyperlipidemia, weight gain, diabetes mellitus, cerebrovascular accidents

• A dose reduction or discontinuation should be considered periodically in patients

• Physical restraints should be limited to patients who pose imminent harm to themselves or others.

Antidepressants

• Citalopram

• Escitiolopram

• Fluoxetine

• Paroxetine

• Sertraline

• Venlafaxine

• Trazadone

• Treatment of depression: poor appetite, insomnia, hopelessness, anhedonia, withdrawal, suicidal thoughts, agitation, or anxiety

• As many as 50% of AD patients suffer from depression

Anticonvulsants

• Carbamazepine

• Valproic Acid

• Treatment of agitation or aggression

Standard of treatment

• None exists

• Duration of treatment ranges from clinicianto clinician. May be months to years

• No clear standard of care for dosing fromclinical trials

• No clear standard of when to discontinuetherapy in very severe stages of AD– Many clinicians do discontinue therapy when the

patient becomes bed ridden

Key Non-pharmacological Methods

•Education

•Preparation

•Communication

• Educating patient and family at the time of diagnosis– Discussion of the course of illness

– Expectations from treatment

– Legal and financial planning including a durable power of attorney

– Quality of life issues

– Re-enforcing the importance of communication between the patient and family members

– Decreasing environmental triggers and personal discomfort

Non-Pharmacological Interventions

• Physical well-being

• Increased overall well being

• Stimulation oriented treatments: recreational activity, art therapy, music therapy, pet therapy and aromatherapy may be useful, but lack of sufficient evidence to validate effectiveness but used in clinical practice

Caregivers

• Find time to rest, relax and tend to personal affairs because stress will impact the health and quality of life of both the patient and the caregiver

• Help patients to discover a structured level of autonomy using reminders and explanations

• Be aware of signs and symptoms of decline

• Knowing when to institutionalize a patient

Interventions

• Patients should be assessed every 3-6 months

• Patients may need to stop driving even at mild levels of treatment

• Sleep disturbances common in people with dementia, proper sleep hygiene should be implemented before beginning pharmacological therapy

Behavioral Management

• Sleep disturbances

• Wandering

• Urinary Incontinence

• Agitation

• Aggression

• May be useful to try this before beginning drug therapy

Epidemiological Correlations

• Brain Vascular Health

• Lipid lowering agents

• Non inflammatory agents

• Vitamin B 6, B12 and B12 deficiency

• Hyerhomocysteinemia

Brain Vascular Health• New studies have evidence brain vascular

disease plays an important role in theprogression of dementia

• Brain vascular disease may acceleratedeposition of β amyloid plaques and increaseamyloid toxicity to neurons and the neuralsynapses

• Brain vascular health includes managing bloodpressure, glucose, cholesterol andhomocysteine.

– Elevated homocysteine levels correlate withdecreased performance on cognitive tests

• Importance of stating physically, mentally, andsocially active

Folate, Vitamin B1, Vitamin B6

• Defects in these vitamins are associatedwith neurological and psychologicaldysfunction

• In elderly patients there is increasedconcern of satiety, atrophic gastritis,and decreased function of the olfactoryfunctions

• Increased homocysteine has a directcorrelation with a deficiency and thesevitamins

Estrogen Therapy

• Epidemiological studies post menopausal women who took estrogen replacement therapy had a lower incidence of AD

• Studies did not show an improvement in behavioral or functional outcomes when estrogen used to treat cognitive decline

• Estrogen has a risk of stroke and other cardiovascular events

Anti-inflammatory Agents

• Epidemiological studies suggest patients on anti-inflammatory agents have a lower incidedence of AD

• Treatment less than 2 years proved beneficial in some patients

• Clinical studies does not show evidence of cognitive benefit and tolerability was an issue

Lipid Lowering Agents

• Epidemiological studies and AD show a correlation between higher midlife total cholesterol rates and AD

• Correlation between people on lipid lowering therapy and lower incidences' of AD– Pravastatin and lovastatin but not simvastatin

were associated with a lower incidence of AD– More trials are needed to address the impact of

cognitive benefit, the duration of treatment, class effect, and optimal dosing for its role in AD

• Role of therapy should remain for people with indications for their use

Therapies in the Pipeline

• Vitamin E

• Atomexetine

• IGIV 10%

• Thiazolidinediones (anti-inflammatory effects)

• Over 900 studies occurring now phase 1-4 and

• Ginkgo Biloba

• Huperzine A

• Semagacestat (LY450139)

• Coenzyme Q10

• Acupuncture

• Over 100 studies phase 3

Vitamin E

• Antioxidant- may be useful because of the accumulation of free radicals associated with AD

• Favorable side effect profile and low cost

• Impaired hemostasis, fatigue, nausea, diarrhea, abdominal pain, and thinning of the blood

• Increased mortality in older patients

• Doses above 400 international units per day should be avoided in patients with AD

• May be beneficial in combination with Selegeline: Phase III study-PREADVISE-examining anti-oxidant effects of Selegeline

Ginkgo Biloba

• Increased blood flow, decreased viscosity of the blood, antagonizing platelet activating factor receptors, increased tolerance to anoxia, inhibiting monoamine oxidase, anti-infective properties, preventing damage of membranes caused by free radicals

• If used for dementia should be used as soon as deterioration of cognitive functioning occurs

• Side effects are typically mild and rare

• Herbal products are typically poorly standardized

Huperzine A

• An alkyloid isolated from the Chinese club moss, Huperzia serrata

• Reversibly inhibits acetylcholinesterase and is administered orally in doses 50-200 mcg 2-4 times daily

• May be more promising for symptomatic treatment of Alzheimer’s disease

• Promising product from clinical studies, but lack of product purity

• Concurrent use with other available cholinesterase inhibitors should be avoided

Semagacestat (LY450139)

• Inhibiting the enzyme gamma-secretase lowers the production of beta amyloid. Semagacestat (LY450139) a functional gamma-secretase inhibitor lowers the beta amyloid in the blood and spinal fluid in humans.

• Effect of LY450139 a gamma-secretase inhibitor on the progression of Alzheimer’s disease as compared with Placebo- Currently Phase III

• 60 mg orally titrated up to 140 mg

Immune Globulin Intravenous (Human), 10% (IGIV, 10%)

• A Randomized, Double-Blind, Placebo-Controlled, Two Dose-Arm, Parallel Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% (IGIV, 10%) for the Treatment of Mild to Moderate Alzheimer's Disease – Phase III trial

• The purpose of this study is to determine whether IGIV, 10% treatment, administered at two different doses results in a significantly slower rate of decline of dementia symptoms in subjects with mild to moderate (AD).

• Approved in 2005 for primary immunodeficiency

Coenzyme Q10

• A natural antioxidant in the body

• Role of therapy currently being explored, but limited clinical trials in humans for AD

Helpful links

• www.aoa.gov

• www.nia.nih/gov/alzheimers

• www.alzforum.org

• www.aarp.gov

• www.thefamilycaregiver.org

• www.ec-online.net

Economic Impact

• US health care cost is greater than $100 billion

• Annual cost for caring for an individual with advanced AD is approximately $50,000

• According to CDC, there is 231,900 patients in nursing homes with AD which accounts for 15.5% of the nursing home population

• 4th leading cause of death in adults

Resources

• http://www.gammagardliquid.com/about-gammagard-liquid/dosage-administration.html

• http://www.nlm.nih.gov/medlineplus/druginfo/natural/1003.html

• cdc.gov

• www.ncbi.nlm.nih.gov

• www.novartis.com

• www.alz.org

• www.clinicaltrials.gov

Resources

• National Guideline Clearinghouse (NGC). Guideline synthesis: Management of Alzheimer's disease and related dementias. In: National Guideline Clearinghouse (NGC). Rockville (MD): 2006 Nov (revised 2010 Sep). [cited 2011 June 13]. Available: http://www.guideline.gov.

• Dipiro J,Talbert R, Yee G., Matzke G, Wells B, Posey L. Pharmacotherapy: A Pathophysiologic Approach. 7th. New York: McGraw-Hill, 2008. 1051-1066

• B Vitamins, Homocysteine, and Neurocognitive Function in the Elderly. American Journal of Clinical Nutrition. February 2000;71(2):614s-620s. Accessed June 15, 2011.

treatment

• Current therapy is aimed at prolonging the patient’s cognitive function and secondary goals include symptomatically treating psychiatric and behavioral abnormalities

• Current therapy has not been shown to prolong life, cure AD, halt or reverse the pathophysiological degradation of the disease

Aricept Used to delay or slow the symptoms of ADDonepezil • Loses its effect over time

• Used for mild, moderate and severe AD

• Does not prevent or cure AD

CelexaCitalopram Used to reduce depression and anxiety

• May take 4 to 6 weeks to work• Sometimes used to help people get to sleep

Used to reduce depression and anxiety• May take 4 to 6 weeks to work• Sometimes used to help people get to sleep

Depakote® (DEP-uh-cote)Sodium valproate (so-DEE-um VAL-pro-ate)

Depakote Used to treat severe aggressionSodium Valproate • Also used to treat depression and anxiety

Exelon Used to delay or slow the symptoms of ADRivastigmine • Loses its effect over time

• Used for mild to moderate AD• Can get in pill form or as a skin

patch• Does not prevent or cure AD

Namenda Used to delay or slow the symptoms of ADMemantine • Loses its effect over time

• Used for moderate to severe AD• Sometimes given with Aricept®,

Exelon®• Does not prevent or cure AD

Razadyne Used to prevent or slow the symptoms of ADGalantamine • Loses its effect over time

• Used for mild to moderate AD• Can get in pill form or as a skin

patch• Does not prevent or cure AD

Zoloft Used to reduce depression and anxietySertraline • May take 4 to 6 weeks to work

• Sometimes used to help people get to sleep

Trileptal Used to treat severe aggressionOxcarbazepine • Also used to treat depression and anxiety

Tegretol Used to treat severe aggressionCarbamazepine • Also used to treat depression and anxiety

Remeron Used to reduce depression and anxietyMirtazepine • May take 4 to 6 weeks to work

• Sometimes used to help people get to sleep

Although there is currently no way to cure Alzheimer'sdisease or stop its progression, researchers are makingencouraging advances in Alzheimer's treatment, includingmedications and non-drug approaches to improvesymptom management.

Mild/Moderate AD:

Cholinesterase inhibitors increase the levels ofacetylcholine in the brain, which plays a key role inmemory and learning. This kind of drug postpones theworsening of symptoms for 6 to 11 months in about half ofthe people who take it. Cholinesterase inhibitors mostcommonly prescribed for mild to moderate Alzheimer'sdisease include Aricept (donezepil HCL), Exelon(rivastigmine), and Razadyne (galantamine).

• Moderate/Severe AD:

Namenda (memantine) regulates glutamate in the brain,which plays a key role in processing information. This drugis used to treat moderate to severe Alzheimer's diseaseand may delay the worsening of symptoms in somepeople. It may allow patients to maintain certain dailyfunctions a little longer than they would without themedication.

Razadyne

• Razadyne (galantamine HBr) is FDA-approved for mild and moderate stages of the disease.

• Razadyne is a cholinesterase inhibitor that prevents the breakdown of acetylcholine in the brain. Acetylcholine plays a key role in memory and learning; higher levels in the brain help nerve cells communicate more efficiently. Razadyne also stimulates nicotinic receptors to release more acetylcholine in the brain.

Razadyne delays the worsening of Alzheimer's symptoms for 6 to 11 months in about half of the people who take it.

Razadyne is available in tablet and capsule form, and is commonly started at 4 mg twice a day. If it's well tolerated after 4 weeks, the dosage may be increased to 8 mg twice a day.

Razadyne also comes in an extended release, once-a-day tablet.

Razadyne is available in generic form (galantamine HBr).

Exelon (Rivastigmine)

Exelon is FDA approved for mild and moderate stages of the disease; it is also approved for the treatment of mild to moderate dementia due to Parkinson's disease.

Exelon is available as a capsule, liquid, and patch.

• Exelon is a cholinesterase inhibitor thatprevents the breakdown of acetylcholineand butyrylcholine in the brain byblocking the activity of two differentenzymes. Acetylcholine andbutyrylcholine play a key role in memoryand learning.

• When given orally, bioavailability is about40% in the 3 mg dose. The compound cancross the blood-brain barrier.

Aricept (Donepizel)

• One of the most widely used drugs to treat the symptoms of Alzheimer's disease. Aricept is FDA-approved for mild, moderate, and severe stages of the disease.

• Aricept is available in tablet form or an orally disintegrating tablet form, and is commonly started at 5 mg a day.

• Can cross the blood-brain barrier.

Namenda (Memantine)

• Namenda is an N-methyl D-aspartate (NMDA) antagonist that regulates the activity of glutamate in the brain. Glutamate plays a key role in memory and learning, but excess glutamate can lead to the disruption of nerve cell communication or nerve cell death.

• Studies involving Namenda have shown that the drug can slow the rate of decline in thinking and the ability to perform daily activities in individuals who have moderate to severe Alzheimer's disease

• A dysfunction of glutamatergic neurotransmission is thought to be involved in the etiology of AD.

• Namenda is available in generic form (memantine HCL).

A molecule designed by a Purdue University researcher to stop the debilitating symptoms of Alzheimer's disease has been shown in its first phase of clinical trials to be safe and to reduce biomarkers for the disease.

The molecule, called a β-secretase inhibitor, prevents the first step in a chain of events that leads to amyloid plaque formation in the brain. This plaque formation creates fibrous clumps of toxic proteins that are believed to cause the devastating symptoms of Alzheimer's.

• Researchers at Mount Sinai School of Medicine have found that a compound called NIC5-15, might be a safe and effective treatment to stabilize cognitive performance in patients with mild to moderate Alzheimer's disease. The two investigators, Giulio Maria Pasinetti, M.D., Ph.D. , and Hillel Grossman, M.D., presented Phase IIA preliminary clinical findings at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD) in Vienna on July 1

• NIC5-15's potential to preserve cognitive performance will be further evaluated in a Phase IIB clinical trial. Early evidence suggests that NIC5-15 is a safe and tolerable natural compound that may reduce the progression of Alzheimer's disease-related dementia by preventing the formation of β-amyloid plaque, a waxy substance that accumulates between brain cells and impacts cognitive function.

http://www.sciencedaily.com/releases/2008/01/080123101629.htm

http://www.sciencedaily.com/releases/2009/07/090712145228.htm

http://www.nia.nih.gov/Alzheimers/Publications/CaringAD/other/medicines.htm

http://en.wikipedia.org/wiki/Rivastigmine

http://en.wikipedia.org/wiki/Galantamine

http://en.wikipedia.org/wiki/Donepezil

http://en.wikipedia.org/wiki/Mementine

Newsweek; 06/15/98, Vol. 131 Issue 24, p52, 2p,

• Harvard Mental Health Letter; Apr2010, Vol. 26 Issue 10, p7-7, 1/2p

• Asian Journal of Animal & Veterinary Advances; 2010, Vol. 5 Issue 1, p13-23, 11p, 1 Chart, 2 Graphs

• Medical Device Daily; 2/16/2010, Vol. 14 Issue 30, p1-6, 2p

• An Introduction to Medicinal Chemistry by Graham L. Patrick, pp. 589-590.

• Abbott, Alison. Neuroscience: The plaque plan. Nature (London, United Kingdom) (2008), 456(7219), 161-164.

• Bolognesi, Maria L.; Matera, Riccardo; Minarini, Anna; Rosini, Michela; Melchiorre, Carlo. Alzheimer's disease: new approaches to drug discovery. Current Opinion in Chemical Biology (2009), 13(3), 303-308.

• What are the three stages of Alzheimer’s Disease?

• What are some of the diagnostic tools of diagnosing Alzheimer’s Disease?

• What drugs are used to treat mild/moderate Alzheimer’s Disease?

• Which drug is most commonly used to treat Alzheimer’s Disease?

• Have current pharmaceutical agents been successful in slowing the progress of Alzheimer’s Disease?

• Why is it important to develop ‘biomarkers’ for Alzheimer’s Disease?