Patrick

An Introduction to Medicinal
Chemistry 3/e
Chapter 19

CHOLINERGICS,
ANTICHOLINERGICS
& ANTICHOLINESTERASES
Part 3: Cholinergics & anticholinesterases

Contents
Part 3: Cholinergics & anticholinesterases
14. Acetylcholinesterase
14.1.
Role
14.2.
Hydrolysis reaction catalysed
14.3.
Effect of inhibition
14.4.
Structure of enzyme complex
14.5.
Active site - binding interactions
14.6.
Active site - Mechanism of catalysis (3 slides)
15. Anticholinesterases
15.1.
Physostigmine
15.2.
Mechanism of action (3 slides)
15.3.
Physostigmine analogues
15.4.
Organophosphates (9 slides)
15.5.
Anticholinesterases as Smart Drugs (2 slides)
[30 slides]

14. Acetylcholinesterase
14.1Role
Hydrolysisanddeactivationofacetylcholine
Preventsacetylcholinereactivatingreceptor

...

Nerve1
Signal

...

Nerve2

...

Acetylcholinesteraseenzyme

14. Acetylcholinesterase
14.2Hydrolysisreactioncatalysed

C
CH3

HO

NMe3

CH3

Acetylcholine

OH

+
Choline

Acetic acid

active

NMe3

inactive

14. Acetylcholinesterase
Enzymeinhibitor
(Anticholinesterase)

14.3Effectofinhibition

2oMessage

Ach

Inhibitorblocksacetylcholinesterase
Achisunabletobind
Achreturnstoreceptorandreactivates
it
Enzymeinhibitorhasthesameeffectas
acholinergicagonist

Nerve2
1

14. Acetylcholinesterase
14.4Structureofenzymecomplex
S

Enzyme
S
S

S
S

Enzyme

S
S

S
S

S
S

Enzyme

14. Acetylcholinesterase
14.5Activesitebindinginteractions
Esterbindingregion

Anionicbindingregion

Serine
OH

Aspartate

Histidine
N

hydrophobic
pockets

vdw Me

:O::

Ionic

CH2

CH2

Hbond
H

CH3

vdwMe
Me

Tyrosine

Anionicbindingregionsimilartocholinergicreceptorsite
BindingandinducedfitstrainsAchandweakensbonds

1
MoleculepositionedforreactionwithHisandSer

14. Acetylcholinesterase
14.6ActivesiteMechanismofcatalysis
O
CH3

:O

:N

:
:O :

CH2CH2 NMe3
NH

CH3

C
O

:N

SerineHistidine
(Nucleophile)(Base)

:
: O:
CH3

C
O

R
H N

NH

Histidine
Acidcatalyst

NH

Histidine
(Basecatalyst)

CH3

C
O

:
:O :
OR
H

:N

NH

Histidine

14. Acetylcholinesterase
14.6ActivesiteMechanismofcatalysis
H2O

CH3

:
:O :

OR

:N

NH

CH3

ROH

Histidine

Histidine

CH3

C
O

NH

: _
: O:

:
:O

:N

NH

CH3

C
O

OH
H

:N

NH

Histidine

Histidine
Basiccatalyst

14. Acetylcholinesterase
14.6ActivesiteMechanismofcatalysis
:

:O :

:O :

CH3

OH

NH

:N

CH3

OH
H

:O :

Histidine
Basiccatalyst
:

Histidine
(Acidcatalyst)

:O :

CH3

NH

O
OH

NH

:N

CH3

C
OH

Histidine

OH

:N

NH

14. Acetylcholinesterase

Serineandwaterarepoornucleophiles

Mechanismisaidedbyhistidineactingasabasiccatalyst

Cholineandserinearepoorleavinggroups

Leavinggroupsareaidedbyhistidineactingasanacidcatalyst

Veryefficient100x106fasterthanuncatalysedhydrolysis

Acetylcholinehydrolysedwithin100 secsofreachingactive
site

Anaspartateresidueisalsoinvolvedinthemechanism

14. Acetylcholinesterase
Thecatalytictriad

Anaspartateresidueinteractswiththeimidazoleringof
histidinetoorientateandactivateit
:

:O

:N

SerineHistidine
(Nucleophile)(Base)

:O:
O
Aspartate

15. Anticholinesterases

Inhibitorsofacetylcholinesteraseenzyme

Blockhydrolysisofacetylcholine

Acetylcholineisabletoreactivatecholinergicreceptor

Sameeffectasacholinergicagonist

15. Anticholinesterases
15.1Physostigmine

O
C O
Me N
H
Urethane
or
Carbamate

Me

Me

Me

PyrrolidineN

NaturalproductfromtheAfricancalabarbean
Carbamateisessential(equivalenttoesterofAch)
Aromaticringisimportant
PyrrolidineNisimportant(ionisedatbloodpH)
PyrrolidineNisequivalenttothequaternarynitrogenofAch

15.2Mechanismofaction

:
O H
:
MeNH

:N

NH

MeNH

O Ar

C O

:N

Ar

NH

:O :
:

Physostigmine

O
MeNH

:
C O: Ar

NH

MeNH

:O :
:

:O :
:

O Ar

:N

NH

15.2Mechanismofaction

ArOH

O
MeNH

:O :
:

O Ar

NH

MeNH

:N
O

Stablecarbamoyl
intermediate

Hydrolysis
veryslow

:N

:N

NH

6
Rateofhydrolysisslowerby40x10

NH

15.2Mechanismofaction

H
O

::

Me

Me

Carbonylgroup
'deactivated'

15.3Physostigmineanalogues
Me

O
C

Me

CH

NMe2

N
H

Me

N
Me

(ionisedatbloodpH)

Miotine

Neostigmine

Simplifiedanalogue
Susceptibletohydrolysis
CrossesBBBasfreebase
CNSsideeffects

NMe3

Fullyionised
CannotcrossBBB
NoCNSsideeffects
Morestableto
hydrolysis
ExtraNmethylgroup
increasesstability
1

Hydrolysismechanisms
Possiblemechanism1

Me

O
+C

OAr

Water

O
Me

: O:

Me

C
N

OH

OAr

OH

MeNH2
+
CO2
1

Hydrolysismechanisms
Possiblemechanism2
O
Me
N

H2O

Me

OAr

Me

MeNH2
+
CO2

OH

Tooreactive
Compare:
O
Me
N

Me
Nohydrolysis

OAr

Me

Myasthenia gravis
Myasthenia gravis (sometimes abbreviated MG; from the Greek myastheneia, lit.
'muscle disease', and Latin gravis, 'serious') is a neuromuscular disease leading to
fluctuating muscle weakness and fatiguability. At about 14 cases per 100,000 (in the
U.S.), it is one of the lesser known autoimmune disorders. Weakness is typically
caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the stimulative effect of the
neurotransmitter acetylcholine. Myasthenia is treated with immunosuppressants,
cholinesterase inhibitors and, in selected cases, thymectomy.

http://www.healcentral.
org/healapp/showMetadata?
metadataId=3621

Me 2 N
Me2N

NMe3

O
O

N
Me

Neostigmine

Pyridostigmine

Treatment
Myastheniagraviscanusuallybecontrolledwithmedication.Medicationisusedfortwo
differentendpoints:
Directimprovementoftheweakness
Reductionoftheautoimmuneprocess
Muscle function is improved by cholinesterase inhibitors, such as neostigmine and
pyridostigmine. These slow the natural enzyme cholinesterase that degrades
acetylcholine in the motor end plate; the neurotransmitter is therefore around longer
to stimulate its receptor. Usually doctors will start with a low dose, eg 3x20mg
pyridostigmine, and increase until the desired result is achieved. If taken 30 minutes
before a meal, symptoms will be mild during eating. Side effects, like perspiration
and diarrhea can be countered by adding atropine. Pyridostigmine is a short-lived
drug with a half-life of about 4 hours.

http://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?
fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable
)+&cid=HTDRUG

http://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?
fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable
)+&cid=HTDRUG

Alzheimer's disease (AD)

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease
characterized by progressive cognitive deterioration together with declining activities of daily
living and neuropsychiatric symptoms or behavioral changes. It is the most common type of
dementia.
The most striking early symptom is loss of short term memory (amnesia), which usually
manifests as minor forgetfulness that becomes steadily more pronounced with illness
progression, with relative preservation of older memories. As the disorder progresses, cognitive
(intellectual) impairment extends to the domains of language (aphasia), skilled movements
(apraxia), recognition (agnosia), and those functions (such as decision-making and planning)
closely related to the frontal and temporal lobes of the brain as they become disconnected from
the limbic system, reflecting extension of the underlying pathological process. These changes
make up the essential human qualities, and thus AD is sometimes described as a disease
where the victims suffer the loss of qualities that define human existence.
This pathological process consists principally of neuronal loss or atrophy, principally in the
temporoparietal cortex, but also in the frontal cortex, together with an inflammatory response to
the deposition of amyloid plaques and neurofibrillary tangles.

http://www.healthcentral.com/alzheimers/introduction7115.html

Et

O
MeO

Me

Me

MeO

Donepezil(Aricept)

NMe 2

Rivastigmine
(Exelon,Novartis)

Acetylcholinesterase inhibitors
Acetylcholinesterase (AChE) inhibition was thought to be important because there is a reduction in activity
of the cholinergic neurons. AChE-inhibitors reduce the rate at which acetylcholine (ACh) is broken down
and hence increase the concentration of ACh in the brain (combatting the loss of ACh caused by the death
of the cholinergin neurons). Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms but
do not alter the course of the underlying dementing process.[67][68][69]
Examples include:
tacrine - no longer clinically used
donepezil - (marketed as Aricept)
galantamine - (marketed as Razadyne in the U.S.A. Marketed as Reminyl or Nivalin in the rest of the world)
rivastigmine - (marketed as Exelon)
There is significant doubt as to the effectiveness of cholinesterase inhibitors. A number of recent articles
have criticized the design of studies reporting benefit from these drugs, concluding that they have doubtful
clinical utility, are costly, and confer many side effects.[70][71] The pharmaceutical companies, but also
some independent clinicians, dispute the conclusions of these articles. A transdermal patch is under
development that may ease administration of rivastigmine.[72]ivastigmine.

15.4 Organophosphates
a)Nervegases
i

PrO

PrO

P
iPrO

P
F

Dyflos
(Diisopropylfluorophosphonate)

Me

Sarin

AgentsdevelopedinWorldWar2
Agentsirreversiblyinhibitacetylcholinesterase
PermanentactivationofcholinergicreceptorsbyAch
Resultsindeath

O
N

VXNerveAgent

The VX nerve agent is the most well-known of the V-series of nerve agents. Its chemical name
is O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothiolate and its molecular formula is
C11H26NO2PS.
The only countries known to possess VX are the United States and Russia. VX agent is
considered an area denial weapon due to its physical properties.
With its high viscosity and low volatility VX has the texture and feel of high-grade motor oil. This
makes it especially dangerous, as it has a high persistence in the environment. It is odorless
and tasteless, and can be distributed as a liquid or, through evaporation, into small amounts of
vapor. It works as a nerve agent by blocking the function of the enzyme acetylcholinesterase.
Normally, an electric nerve pulse would cause the release of acetylcholine over a synapse that
would stimulate muscle contraction. The acetylcholine is then broken down to non-reactive
substances (acetic acid and choline) by the acetylcholinesterase enzyme. If more muscle
tension is needed the nerve must release more acetylcholine. VX blocks the action of
acetylcholinesterase, thus resulting in sustained contractions of all the muscles in the body.
Sustained contraction of the diaphragm muscle causes death by asphyxiation.

O
N

VXNerveAgent

Often regarded as the deadliest nerve agent created to date, as little as 200 micrograms is
enough to kill an average person, depending on method of absorption. Death can be avoided if
the appropriate antidote is injected immediately after exposure. The most commonly used
antidote is atropine and pralidoxime, which is issued for military personnel in the form of an
autoinjector. Standard chemical agent resistance pills are also effective. Atropine works by
binding and blocking a subset of acetylcholine receptors (known as muscarinic acetylcholine
receptor, mAchR), so that the build up of acetylcholine produced by loss of the
acetylcholinesterase function can no longer affect their target. This prevents involuntary
muscle actions so that muscles like the diaphragm are not in constant contraction. The
injection of pralidoxime regenerates bound acetylcholinesterase.

The chemist Ranajit Ghosh discovered the V-series nerve agents at the government research
establishment at Porton Down, England in 1952; VX was passed over in favour of continuing with
sarin as their chemical weapon of choice. The United Kingdom unilaterally renounced chemical and
biological weapons in 1956. In 1958 the British government traded their research on VX technology
with the United States of America in exchange for information on thermonuclear weapons. The US
then went into production of large amounts of VX in 1961.

The US later destroyed all of its stockpiles of the deadly nerve agent (by incineration at Johnston
Island in the South Pacific), as mandated by the US accession to the Chemical Weapons Convention.
Earlier, pre-treaty disposal included the US Army's CHASE (Cut Holes And Sink 'Em) program, in
which old ships were filled with chemical weapons stockpiles and then scuttled. CHASE 8 was
conducted on June 15, 1967, in which the S.S. Cpl. Eric G. Gibson was filled with 7,380 VX rockets
and scuttled in 7,200 feet of water, off the coast of Atlantic City, New Jersey. The long-term
environmental ramifications of exposing large quantities of VX to seawater and marine life could pose
a grave danger, but are ultimately unknown.

The US is also destroying chemical weapons stockpiles containing VX in nine other locations, one of which
is in Russia. On June 12, 2005, it was reported that more than 250,000 US gallons (950 m) of the chemical
weapon are stored at the Newport Chemical Depot in Newport, Indiana, about 30 miles (50 km) north of
Terre Haute, Indiana. The VX is in the process of being hydrolyzed to much less toxic byproducts using
concentrated caustic solution. The VX hydrolysate produced will contain mainly a phosphonate ester and a
thiolamine, with 20 parts per billion or less of residual VX. (Interestingly, 20 ppb is the level of VX in water
that is considered permissible for drinking by US combat troops.)
A plan was developed to truck the hydrolysate from Indiana to the DuPont Chambers Works Secure
Environmental Facility at Deepwater, NJ where it was to be further treated to destroy the phosphonate ester
and the thiolamine, and dumped into the Delaware River.[2] The governors of Delaware, New Jersey,
Pennsylvania, and New York have opposed this plan and the New Jersey Governor Codey instructed the
New Jersey Department of Transportation to deny entry to any trucks carrying the hydrolysate to the
Deepwater facility. Prior to the current plan, it had been proposed that the hydrolysate be dumped into the
Great Miami River, a tributary of the Ohio River, near Dayton, Ohio but the community there successfully
defeated the proposal.
VX hydrolysis began on May 5 2005 and as of June 12 the facility had destroyed 2,894 US gallons (11 m)
of VX. A contained spill of 30 US gallons (100 L) drew attention to the disposal process, but authorities said
no agent was released and no one was injured in the spill.
Iraq under Saddam Hussein admitted to UNSCOM that it had researched VX, but denied weaponizing the
agent due to production failure. [1] Subsequent investigation after the 2003 Invasion of Iraq indicates that
Iraq had indeed weaponized VX in 1988 and had dropped three VX-filled bombs on Iran. [2]

15.4 Organophosphates
b)Mechanismofaction
H

Serine

Serine

O
i

iPrO
iPrO

PrO

iPrO

P
F

STABLE

Irreversiblephosphorylation
PObondverystable

15.4 Organophosphates
c)Medicinalorganophosphate
O
Me 3N

CH2

CH2

OEt

Ecothiopate

OEt

Usedtotreatglaucoma
Topicalapplication
QuaternaryNisaddedtoimprovebindinginteractions
Resultsinbetterselectivityandlower,saferdoses
O
N

P
S

VXNerveAgent

15.4 Organophosphates
d)Organophosphatesasinsecticides
EtO

MeO
P

P
EtO

NO 2

MeO

CO 2Et
CH
CH2 CO2Et

Parathion

Malathion

Relativelyharmlesstomammals
Agentsactasprodrugsininsects
Metabolisedbyinsectstoproduceatoxicmetabolite

15.4 Organophosphates
d)Organophosphatesasinsecticides
MAMMALS
EtO

EtO

P
EtO

INSECTS

NO 2

PARATHION
(InactiveProdrug)

Insect
Oxidative
desulphurisation

O
P

EtO

NO 2

Activedrug
Mammalian
Metabolism
EtO

Phosphorylatesenzyme

S
P

EtO

OH

INACTIVE
&excreted

DEATH

S
N
N

OEt
P

OEt

Diazinon

http://www.physioviva.com/movies/neurotoxic_insecticides/index.html

N
N

Me
N

Cl

Nicotine

NO2

NH

Imidacloprid

15.4 Organophosphates
e)DesignofOrganophosphateAntidotes
Strategy
StrongnucleophilerequiredtocleavestrongPObond
Findsuitablenucleophilecapableofcleavingphosphateesters
Wateristooweakasanucleophile
Hydoxylamineisastrongernucleophile
O

O
NH 2 OH +

RO P OR

Hydroxylamine

OR

H2 N

O P OR

ROH

OR

Hydroxylamineistootoxicforclinicaluse
Increaseselectivitybyincreasingbindinginteractionswithactive
site

15.4 Organophosphates
e)DesignofOrganophosphateAntidotes

CH N

CH3

Pralidoxime
OH

QuaternaryNisaddedtobindtotheanionicregion
Sidechainisdesignedtoplacethehydroxylaminemoietyin
thecorrectpositionrelativetophosphorylatedserine
Pralidoxime1milliontimesmoreeffectivethan
hydroxylamine
CannotactinCNSduetochargecannotcrossbbb

15.4 Organophosphates
e)DesignofOrganophosphateAntidotes

O
N
Me

CH N

O
P

CO2

Me

CH N

OR

OR

OR
OR

CO2

OH

SER

ActiveSite(Blocked)

SER

ActiveSite(Free)

15.4 Organophosphates
e)DesignofOrganophosphateAntidotes
H

ProPAM
NOH

N
CH3

Prodrugforpralidoxime
PassesthroughBBBasfreebase
OxidisedinCNStopralidoxime

http://www.superstock.com/ImagePreview/1245W477

15.5 Anticholinesterases as Smart Drugs

ActinCNS

Mustcrossbloodbrainbarrier

UsedtotreatmemorylossinAlzheimersdisease

Alzheimerscausesdeteriorationofcholinergicreceptorsin
brain

SmartdrugsinhibitAchhydrolysistoincreaseactivityat
remainingreceptors

NMe2

Et

CH
15.5 Anticholinesterases as Smart MeDrugs

Me

Cl

O
MeO
NH2

CH 2

Rivastigmine(Exelon)
(analogueofphysostigmine)

N
H

MeO

Donepezil

Tacrine(Cognex)
Toxicsideeffects

H
N

O
P
MeO
MeO

HO

Anabaseine
(antsandmarineworms)

CCl3
OH

Metrifonate
(organophosphate)

O
MeO

S
N

N
Me

Me

Galanthamine
(daffodilandsnowdropbulbs

N
Me

Xanomeline

Nootropics
Nootropics (from Greek, 'acting on the mind'), popularly referred to as "smart drugs", are
substances which boost human cognitive abilities (the functions and capacities of the brain). The
word nootropic is derived from the Greek words noos or "mind" and tropein meaning "to ward."
Typically, nootropics are alleged to work by increasing the brain's supply of neurochemicals
(neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or by
stimulating nerve growth.
Most alleged nootropic substances are nutrients or plant components (herbs, roots, beans, bark,
etc.), available over the counter at health food and grocery stores, and are used as nutritional
supplements. Some nootropics are drugs, used to treat people with cognitive learning difficulties,
neural degradation (Alzheimer's and Parkinson's), and for cases of oxygen deficit to prevent
hypoxia. These drugs have a variety of human enhancement applications as well, are marketed
heavily on the World Wide Web, and are used by many people in personal cognitive
enhancement regimens.
With some nootropics the effects are subtle and gradual, such as with most nerve growth
inducers, and may take weeks or even months before any cognitive improvement is noticed. At
the other end of the spectrum are nootropics which have effects that are immediate, profound,
and obvious. While scientific studies support some of the claimed benefits, it is worth noting that
many of the claims attributed to a variety of nootropics have not been formally tested.

Dementia
Definition
The term dementia refers to symptoms, including changes in memory, personality, and
behavior, that result from a change in the functioning of the brain. These declining changes
are severe enough to impair the ability of a person to perform a function or to interact
socially. This operating definition encompasses 7080 different typesentia. They include
changes due to diseases (Alzheimer's and Creutzfeld-Jakob diseases), changes due to a heart
attack or repeated blows to the head (as suffered by boxers), and damage due to long-term
alcohol abuse.
Dementia is not the same thing as delirium or mental retardation. Delirium is typically a brief
state of mental confusion often associated with hallucinations. Mental retardation is a
condition that usually dates from childhood and is characterized by impaired intellectual
ability; mentally retarded individuals typically have IQ (intelligence quotient) scores below
70 or 75.
Description
The absent-mindedness and confusion about familiar settings and tasks that are hallmarks of
dementia used to be considered as part of a typical aging pattern in the elderly. Indeed,
dementia historically has been called senility. Dementia is now recognized not to be a normal
part of aging. The symptoms of dementia can result from different causes. Some of the
changes to the brain that cause dementia are treatable and can be reversed, while other
changes are irreversible.

The elderly are most prone to dementia, particularly those at risk for a stroke. The historical
tendency of women to live longer than men has produced a higher prevalence of dementia in
older women. However, women and men are equally prone to dementia. Over age 80, more
than 20% of people have at least a mild form of dementia.

Dementia is especially prominent in older people. The three main irreversible causes are
Alzheimer's disease, dementia with Lewy bodies, and multi-infarct dementia (also called
vascular dementia).

What type of drugs will enhance cognition?

Neurotransmitter support - supplying the body with the precursors and cofactors it needs to
produce neurotransmitters. Keeping the brain's neurotransmitters at high levels improves
concentration, mental focus, calculation ability, memory encoding, recall, creativity, mood, and
cures and prevents most depressions. The four main neurotransmitters are acetylcholine,
dopamine, norepinephrine and serotonin.
Note that cardiovascular exercise performed on a regular basis also has nootropic effects, by
increasing the body's capacity to supply brain cells with oxygen. Exercise is highly synergistic
with nutritional supplementation, and a health regimen is incomplete without it.

Cholinergics are substances which affect the neurotransmitter acetylcholine or the components
of the nervous system which utilize acetylcholine. Acetylcholine facilitates memory,
concentration, focus, and high-order thought processes (abstract thought, calculation,
innovation, etc.). Increasing the availability of this neurotransmitter in the brain may improve
these functions and increase the duration in which they may be engaged without slowing down
or stopping. Oversupplying the brain with acetylcholine may have the opposite effect,
temporarily reducing rather than improving mental performance.

Examples of Cholinergic Nootropic Drugs

AcetylLcarnitine(ALCAR)Aminoacid.Precursorof
acetylcholine(donatingtheacetylportiontotheacetylcholine
molecule).Itissynergisticwithlipoicacid.
Centrophenoxine(Lucidril)Drug.cholinergicagent,enhances
colorperception.
Cholineprecursortoacetylcholine(anessentialcomponentofthe
acetylcholinemolecule).
AlphaGPC(Lalphaglycerylphosphorylcholine,Choline
alfoscerate)mosteffectivecholineprecursor,readilycrossesthe
bloodbrainbarrier.
CDPCholine(CytidineDiphosphateCholine)cholineprecursor,
tendstobelessexpensiveandsimilarineffecttoAlphaGPC.
Cholinebitartrateprecursorofacetylcholine,generalnootropic,
antidepressant.
Cholinecitrateprecursoroftheneurotransmitteracetylcholine,

1
generalnootropic,antidepressant.

O
NH2

Piracetam(brandname:Nootropil,Myocalm)

Piracetam (brand name: Nootropil, Myocalm), is a cerebral function regulating drug which is claimed to be able to
enhance cognition as well as slow down brain aging. Piracetam's chemical name is 2-oxo-pyrrolidone, or 2-oxo-1pyrrolidine acetamide. Piracetam is a cyclic derivative of GABA. It is one of the racetams, and is similar to the amino
acid pyroglutamate. Though rare in the United States, piracetam is commonly prescribed in Europe for a variety of
conditions.
Several meta-reviews of literature on piracetam indicate that piracetam increases performance on a variety of cognitive
tasks among dyslexic children, though this may reflect its enhancement of cross-hemispheric communication and of
cognitive function in general, rather than a specific improvement in whatever causes dyslexia. Piracetam also seems to
inhibit brain damage caused by a variety of factors including hypoxia and excessive alcohol consumption.[1] [2]
Piracetam has been studied in an extensive number of clinical experiments, and has shown positive results in the
treatment of post-stroke aphasia, epilepsy, cognitive decline following heart and brain surgery, dementia[3], and
myoclonus,[4] [5]and some believe that understanding the mechanism through which it works can teach us about the
role of inter-hemispheric communication in the brain.

Aphasia
Definition
Aphasia is a communication disorder that occurs after language has been developed, usually
in adulthood. Not simply a speech disorder, aphasia can affect the ability to comprehend the
speech of others, as well as the ability to read and write. In most instances, intelligence per
se is not affected.
Description
Aphasia has been known since the time of the ancient Greeks. However, it has been the focus
of scientific study only since the mid-nineteenth century. Although aphasia can be caused by
a head injury and neurologic conditions, its most common cause is stroke, a disruption of
blood flow to the brain, which affects brain metabolism in localized areas of the brain.

Myoclonus
Definition
Myoclonus is a brief, rapid, shock-like jerking movement.
Description
Myoclonus can be a symptom of a separate disorder, or can be the only or primary
neurological finding, in which case it is termed "essential myoclonus." Myoclonus may occur in
epilepsy, or following many different types of brain injury, such as lack of oxygen, stroke,
trauma, or poisoning. Myoclonus can occur in one or more limbs, or may be generalized,
involving much of the brain.

Infarction
The process of anoxic tissue death. The usual cause is occlusion of an artery by a
thrombus or embolus and sometimes by severe atherosclerosis.