nzylacetamides Synthesis Spectroscopic
`2-Substituted-2-acetamido-N-be
`and Anticonvulsant Properties
`
`Thesis
`
`Presented
`
`to
`
`the Faculty of
`
`the Department
`
`of Chemistry
`
`University of Houston-University Park
`
`In Partial Fulfillment
`
`of
`
`the Requirements
`
`for
`
`the Degree
`
`Master
`
`of Science
`
`By
`
`Philippe
`
`Le GaD
`
`December 1987
`
`ALEMBIC - EXHIBIT 1008
`
`
`2-Substituted-2-acetamido-N-be
`and Anticonvulsant Properties
`
`Thesis
`
`Presented
`
`to
`
`the Faculty of
`
`the Department
`
`of Chemistry
`
`University of Houston-University Park
`
`In Partial Fulfillment
`
`of
`
`the Requirements
`
`for
`
`the Degree
`
`Master
`
`of Science
`
`By
`
`Philippe
`
`Le GaD
`
`December 1987
`
`ALEMBIC - EXHIBIT 1008
`
`
`
`2-Substituted-2-acetamido--benzylacetamides
`and Anticonvulsant Properties
`
`Synthesist Spectroscopic
`
`ii
`
`Philippe
`
`Le
`
`all
`
`APPROVED
`
`Dr Harold
`
`Kohn
`
`Dr Doudias
`
`Dykes
`
`Dr Thomas
`
`Lemke
`
`Dr
`
`nard
`
`Pettitt
`
`Dean Coil
`
`of Natural Sciences and Mathematics
`
`
`
`ACKNOWLEDGEMENT
`
`would
`
`like
`
`to
`
`thank Dr
`
`Kohn whose
`
`enthusiasm and
`
`knowledge were
`
`always
`
`on my side when
`
`needed
`
`also want
`
`to
`
`thank
`
`all
`
`the
`
`past
`
`and
`
`present members of
`
`this
`
`research
`
`group
`
`am indebted
`
`to
`
`their
`
`friendship and assistance
`
`would like to acknowledge
`
`all
`
`those who
`
`have
`
`contributed
`
`to the completion of
`
`this work
`
`In
`
`particular
`
`would
`
`like
`
`to thank
`
`Dr Gary
`
`Martin
`
`and
`
`the
`
`laboratory at
`
`the University of
`
`Houston Dr
`
`John Chinn
`
`at
`
`the University
`
`of Texas at Austin and
`
`Dr
`
`David
`
`Leander
`
`and Dr
`
`David
`
`Robertson
`
`at
`
`the Eli
`
`Lilly
`
`Research Center
`
`Indianapolis
`
`Indiana for
`
`their kind cooperation
`
`Finally would
`
`like to thank Dr Kurt
`
`Loening Director of
`
`Nomenclature Chemical Abstracts
`
`Services Columbus Ohio for his
`
`help in naming
`
`the synthesized compounds
`
`III
`
`
`
`2-Substituted-2-acetamidobenzylacetamides Synthesis Spectroscopic
`and Anticonvulsant Properties
`
`An Abstract of
`
`Thesis
`
`Presented
`
`to
`
`the Faculty of
`
`the Department of Chemistry
`
`University of Houston-University Park
`
`In Partial Fulfillment
`
`of
`
`the Requirements
`
`for
`
`the Degree
`
`Master
`
`of Science
`
`By
`
`Philippe
`
`Le Gall
`
`December 1987
`
`iv
`
`
`
`ABSTRACT
`
`Select
`
`functaonahzed
`
`amino acid
`
`denvatives
`
`of
`
`the potent anti
`
`convulsant
`
`agent
`
`u-acetamido-fj-be nzylphe nylacetamide
`
`2-acetamido-J-benzylpropionamide
`
`have been
`
`prepared
`
`and
`
`and
`
`evaluated
`
`Attention
`
`has
`
`been
`
`focused
`
`on the replacement of
`
`the
`
`a-phenyl
`
`and a-methyl groups
`
`in 68a and 68b by five-membered nng
`
`hetereoaromatic moieties benzo-fused
`
`heteroaromatic groups
`
`and
`
`simple polar substituents
`
`The synthetic
`
`and
`
`pharmacological
`
`studies revealed
`
`several
`
`notable
`
`findings
`
`First
`
`the use of
`
`amidoalkylation
`
`procedures using
`
`boron trifluoride etherate
`
`provided
`
`straightforward
`
`and
`
`reliable
`
`method
`
`to
`
`introduce
`
`an electron-nch
`
`heteroaromatic
`
`substituent
`
`at
`
`the
`
`a-carbon
`
`in
`
`the
`
`amino acid derivatives
`
`This
`
`technology
`
`permitted
`
`the
`
`incorporation
`
`of
`
`acid
`
`sensitive
`
`unsubstituted
`
`i.e pyrrole
`
`indole Z2 and
`
`heteroaromatic
`
`compounds
`benzoiuran Zn within
`
`the molecule
`
`Second all
`
`the five-membered
`
`ring
`
`heteroaro matic
`
`analogues
`
`of
`
`a-acetamido-ILbenzylphenyIaceta
`
`mide
`
`proved
`
`highly active
`
`in the MES seizure test
`
`In particular
`
`a-acetamido-j-benzyl-2-fu ranacetamide
`
`and
`
`cz-aceta
`
`mido-1i-benzyl-2-pyrroleacetamide
`
`9.b exhibited activities
`
`similar to
`
`phenytoin
`
`and
`
`diazepam Third the a-alkoxy derivatives
`
`2-aceta-
`
`mido-tj-benzyl-2-methoxyacetamide
`
`and 2-acetamido-tt-benzyI-2-
`
`ethoxyacetamide exhibited
`
`significant
`
`activity in
`
`the MES seizure test
`
`
`
`Fourth
`
`neither
`
`the
`
`benzo-fused
`
`heteroaromatic
`
`derivatives
`
`nor
`
`the
`
`compounds
`
`bearing
`
`an
`
`electron-withdrawing
`
`substituent
`
`at
`
`the
`
`a-carbon
`
`had significant
`
`activity
`
`Fifth the composite
`
`pharmacolog
`
`ical
`
`data suggested
`
`that
`
`small
`
`substituents
`
`are
`
`required
`
`at
`
`the
`
`a-carbon
`
`of
`
`the
`
`2-acetamido-j-benzylglycine
`
`denvative
`
`for maximal
`
`activity in
`
`the MES test
`
`and
`
`that
`
`this
`
`activity
`
`is
`
`enhanced
`
`by
`
`the
`
`presence
`
`of electron-donating
`
`groups at
`
`this site
`
`
`
`Aqknowledgements
`List of Tables
`List of Schemes
`List of Figures
`Introduction
`
`TABLE OF CONTENTS
`
`iii
`
`Viii
`
`xiii
`
`xiv
`
`ii
`
`III
`iv
`
`vi
`vii
`viii
`
`the Epileptic Seizure
`of
`Biogenesis
`Symptomatology and Classification of
`Epileptic Seizures
`13
`Evaluation of Anticonvulsant Agents
`17
`Antiepileptic Drugs
`25
`Clinical Applications
`30
`Mechanism of Drug Action
`32
`Relationships
`Structure-activity
`Anticonvulsant Amino Acids and Amino 35
`Acid Derivatives
`Synthesis Spectroscopic and Anticonvulsant Proper-
`of 2-Acetamidoben-
`ties of Structural Analogues
`and 2-Acetamido-tI-benzy
`zyiphenylacetamide
`2-alkoxyacetamides
`
`Chapter
`
`Chapter ii
`
`44
`
`Introduction
`Results and Discussion
`
`ii
`
`Synthesis
`Spectral Evaluation
`Infrared Spectra
`Mass Spectral Data
`1H NMR Spectral Data
`13C NMR Spectral Data
`Evaluation
`Pharmacological
`iii
`Experimental Section
`Synthesis Spectroscopic and Anticonvulsant Proper-
`ties of Polar Analogues 1QZ of 2-Acetamido-N-ben-
`zylpropionamide
`Introduction
`Results and Discussion
`Synthesis
`Spectral Evaluation
`Infrared Spectra
`
`ii
`
`44
`47
`47
`74
`74
`79
`80
`93
`102
`109
`132
`
`132
`132
`132
`139
`139
`
`
`
`Mass Spectral Data
`NMR Spectral Data
`13C NMR Spectral Data
`Evaluation
`Pharmacological
`Experimental Section
`
`144
`144
`147
`153
`155
`164
`166
`
`iii
`General Conclusions
`References
`
`viii
`
`
`
`LIST OF TABLES
`
`Table
`
`Page
`
`The International Classification of Epileptic Seizures
`
`The Revised Classification of Epilpetic Seizures.
`
`Sequential Test Phases Utilized for the Anticonvulsant
`the Antiepileptic Drug Develop
`of
`Screening Project
`ment Program
`
`Antiepileptic Drugs Marketed in the United States
`
`5a
`
`5b
`
`Monocyclic Heteroaromatic
`Analogues
`2-Acetamido--benzyIphenylacetamide
`
`Benzofused Heteroaromatic
`
`Analogues
`2-Acetamido-I1-benzylphenyIacetamide
`
`of
`
`of
`
`Examples of Amino Acids with an a-Heterocyclic
`Substitue nt
`
`18
`
`29
`
`45
`
`46
`
`48
`
`Synthesis of Amino Acid Derivatives
`alkylation Technique
`
`by the Amido-
`
`50
`
`Amidoalkylation
`
`2-Methylfuran
`
`Reactions
`lob
`
`Amidoalkylation Reactions
`Substituted Pyrroles
`
`Involving Furan ZQ and
`
`Involving Pyrrole 24 and
`
`10.
`
`Amidoalkylation Reactions
`
`Involving
`
`lndole 22
`
`11
`
`12
`
`Amidoalkylation
`
`Reactions
`
`Involving Thiophene Zfl
`
`Amidoalkylation
`
`Reactions
`
`Involving Other Heterocycles
`
`53
`
`55
`
`56
`
`57
`
`58
`
`ix
`
`
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`.1
`
`Selected Physical and Spectral Data for Alkyl 2-Aceta-
`mido-2-alkoxyacetate WQ
`
`Selected Physical and Spectral Data for a-Substitu-
`j.
`ted Alkyl 2-Acetamidoacetates
`
`Selected Physical and Spectral Data for a-Substitu-
`ted
`2-Acetamidoacetic
`Acids
`
`Physical and Spectral Data for aSubstitu-
`Selected
`ted 2-Acetamidobenzylacetamides
`
`61
`
`62
`
`64
`
`67
`
`Selected Physical and Spectral Data
`Ii-benzyl-2-alkoxyacetamides
`
`for 2-Acetamido-
`
`69
`
`Reactions
`
`Companson
`Invol- 73
`of Several Amidoalkylation
`Thiophene Z1 lndole
`ving Furan ZQa Pyrrole
`and Benzo
`ZZ Benzofuran
`Be
`ginning with Either
`
`and
`
`or 86b
`
`Selected Infrared Spectral Data for Alkyl 2-Acetamido-2- 75
`alkoxyacetates EQ
`
`Selected Infrared Spectral
`jj
`-2--acetamidoacetates
`
`Data for Alkyl 2-Substituted
`
`Selected Infrared Spectral Data for 2-Substituted-2-ace-
`tamidoacetic
`Acids
`
`Selected Infrared
`
`Spectral Data for 2-Substituted-2-ace-
`tamido--benzylacetarnides
`
`NMR Spectral Properties
`alkoxyacetates EQ.
`
`for Alkyl 2-Acetamido-2-
`
`1H NMR
`Spectral Properties for Alkyl 2-Substituted-2-
`Acetamidoacetates
`
`76
`
`77
`
`78
`
`86
`
`87
`
`
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`1H NMR Spectral Properties for 2-Substituted-2-aceta-
`midoacetic Acids 82
`
`NMR Spectral Properties for 2-Substituted-2-aceta-
`midobenzylacetamides
`
`13C NMR Spectral Properties for Alkyl 2-Acetamido-
`2-alkoxyacetates aQ
`13C NMR Spectral Properties for Alkyl 2-Acetamido-
`2-acetamidoacetates
`8i..
`
`13C NMR Spectral Properties for Alkyl 2-Substituted-
`Acids 82
`2-acetamidoacetic
`
`13C NMR Spectral Properties for 2-Substituted-2-aceta-
`8g
`mido-j-benzylacetamides
`
`of 2-Substituted-2-acetamt-
`Evaluation
`Pharmacological
`do-t-benzylacetamides 89 Containing
`Monocyclic He
`terocyclic Moiety
`
`Evaluation
`Pharmacological
`do--benzylacetamides
`Heterocyclic Moiety
`
`of 2-Substituted-2-acetami-
`Benzo-fused
`
`Containing
`
`Evaluation
`Pharmacological
`benzylacetamides 8k
`
`of 2-Alkyl-2-acetamido-
`
`89
`
`90
`
`94
`
`95
`
`96
`
`98
`
`104
`
`105
`
`106
`
`Pharmacological
`sants
`
`Activity of Some Proven Anticonvul-
`
`107
`
`2-Acetamido--benzylpropionamide
`
`Analogues
`
`jQZ
`
`Selected Physical and Spectral Properties for
`the P0-
`of 2-Acetamido--be azylpropio nam ide
`lar Analogues
`8fla
`
`133
`
`137
`
`xi
`
`
`
`37
`
`38
`
`39
`
`40
`
`41
`
`42
`
`43
`
`44
`
`Selected Physical and Spectral Data for Oxazole De-
`rivatives ill
`and 11.4.
`
`Selected Infrared Spectral Data for
`the Polar Analo-
`07a-e of 2-Acetamido-N-benzylpropionamide
`gues
`fi
`
`Selected Physical and Spectral Data for Oxazole De-
`rivatives iii
`and 114.
`
`NMR Spectral Properties for
`of 2-Acetamido-tj-benzytpropionamide fi
`07a-e
`1H NMR Spectral Properties for the Oxazole Deriva-
`fliand 114.
`tives
`
`the Polar Analogues
`
`13C NMR Spectral Properties for
`07a-e
`gues
`of 2-Acetamido-j-be nzylpropionamide
`
`the Polar Analo-
`
`141
`
`142
`
`143
`
`145
`
`148
`
`149
`
`l3 NMR Spectral Properties
`tives 111 and 114
`
`for Oxazole Deriva-
`
`151
`
`Pharmacological
`of
`
`Evaluation
`
`of
`
`2-Acetamido-j-benzyIpropionamide Ba
`
`the Polar Analogues
`
`154
`
`xii
`
`
`
`LIST OF SCHEMES
`
`Scheme
`
`Page
`
`Synthesis of 2-Substituted-2-acetamido--benzyl-
`a.b.f.h by Method
`acetamides
`
`Preparation
`Acid
`
`of a-Acetamido-2-benzo
`
`Synthesis of 2-Substituted-2-acetamido-li-benzylaceta-
`mides 69 a.b.i-h by Method
`
`Acid Catalysed Trirnerization of
`
`lndole Zn
`
`Selected Mass Spectral Patterns Observed for AIkyl-2-
`.81
`substituted-2-acetamidoacetates
`
`Selected Mass Spectral Cleavage Patterns Observed
`for 2-Substituted-2-acetamidobenzylacetamides
`
`Selected Mass Spectral Cleavage Patterns Observed
`for Alkyl
`2-Acetamido-2-alkoxyacetates
`
`Selected Mass Spectral Patterns Observed for 2-
`Substituted-2-acetamidoacet
`ic Acids
`
`59
`
`65
`
`68
`
`72
`
`81
`
`82
`
`83
`
`84
`
`the Polar Analogues
`Preparation of
`Acetamido--benzylpropionamide
`
`107a-e
`
`of 2-
`
`134
`
`10
`
`11
`
`12
`
`of 5-Ethoxy-2-methyloxazole-4-carboxylic
`Preparation
`Acid -Benzylamide 111
`
`of 5-Amino-2-rnethyloxazole-4-carboxylic
`Preparation
`Acid
`fl-Benzylamide
`
`Proposed Mechanism for
`the Conversion
`jQZ to the Oxazole Derivative
`pound
`
`of Corn-
`jfl
`
`138
`
`138
`
`140
`
`
`
`LIST OF FIGURES
`
`Figure
`
`Page
`
`Prespective
`conformations
`pam Left
`
`the Three-dimensional
`Drawing of
`and Diaze
`of Phenyttoin Right
`
`Amino Acids and Amino Acid Derivatives
`Excitatory Neurotransmission
`
`acting with
`
`Inter-
`
`Amino Acids and Amino Acid
`Derivatives
`acting with the GABAergic System GABA Prodrugs
`
`Inter-
`
`Amino Acids and Amino Acid Derivatives
`Inter-
`acting with the GABAergic System Compounds
`Umiting GABA Uptake
`
`Amino Acids
`and Amino Acid Derivatives
`acting with the GABAergic System GABA Re
`ceptors Agonists
`
`Inter-
`
`34
`
`37
`
`38
`
`40
`
`41
`
`iv
`
`
`
`INTRODUCTION
`
`Epilepsy
`
`is
`
`major neurological disorder It affects at
`
`least 0.5
`
`percent of
`
`the world
`
`population1 .2 and its symptoms generally appear
`
`early in life.1
`
`If
`
`the origin of
`
`the disease is unknown it
`
`is termed
`
`idiopathic Correspondingly when the epilepsy
`
`is of
`
`known origin the
`
`disease is
`
`referred to as
`
`symptomatic.3 In the latter situation prenatal
`
`and postnatal
`
`trauma brain tumor and vascular disorders are the major
`
`etiologies associated with
`
`the disease.13
`
`The occurrenôe of seizures
`
`is
`
`the manisfestation of epilepsy
`
`Seizures may
`
`be
`
`of different
`
`types
`
`and may have sensory motor and autonomic components
`
`Historically epilepsy
`
`has
`
`been
`
`referred
`
`to as
`
`the
`
`dread
`
`disease the Sacred Disease the falling sickness
`
`or St Johns
`
`disease
`
`Hammurabi
`
`It
`
`was mentioned
`
`in
`
`the
`
`babylonian
`
`civil
`
`code
`
`of
`
`akkadian
`
`and
`
`2080 B.C and
`
`early
`
`hebrew
`
`texts
`
`Hippocrates Ca 400 B.C wrote the first monograph on the affliction and
`
`first
`
`anticipated its brain origin.34
`
`Despite the early recognition
`
`of
`
`this disease significant activity
`
`directed
`
`towards
`
`the
`
`treatment
`
`and
`
`the
`
`understanding
`
`of epilepsies
`
`began
`
`in earnest
`
`in the mid-nineteenth century.135
`
`In
`
`1870 H.J
`
`Jackson
`
`described
`
`epilepsy as an occasional
`
`and abnormally intense
`
`disorderly discharge
`
`of nervous tissue of which
`
`the
`
`seizures are the
`
`symptom.3
`
`This statement
`
`is still
`
`accepted
`
`today Our knowledge
`
`of
`
`the brain malfunction
`
`has not permitted
`
`more detailed definition
`
`It
`
`is
`
`generally
`
`accepted
`
`that
`
`epilepsy
`
`is
`
`reserved
`
`for
`
`those
`
`diseases
`
`
`
`manisfesting
`
`themselves
`
`by
`
`chronic
`
`occurrence
`
`of
`
`seizures
`
`Accordingly seizures elicited
`
`by punctual
`
`factors
`
`such as alcohol and
`
`drug intoxication
`
`or withdrawal are not considered to be
`
`form of
`
`this
`
`disease
`
`Biogenesis
`
`of
`
`the Epileptic Seizures
`
`Although
`
`the neurophysiology of
`
`the central
`
`nervous
`
`system
`
`and
`
`the biochemical
`
`processes
`
`associated with
`
`neuronal
`
`activity
`
`are
`
`now fairly well established68
`
`the
`
`key
`
`events
`
`leading
`
`to epileptic
`
`activity have
`
`not been determined
`
`It was early recognized that epilepsy
`
`may affect only
`
`part of
`
`the brain at
`
`the onset
`
`Subsequently the
`
`existence
`
`of epileptic
`
`Levine9 demonstrated
`
`revealed.7
`
`in 1975 Ebersole
`foci were
`and
`that Enhanced Physiological Response EPR of
`
`neurons
`
`submitted
`
`application
`
`could
`
`to an epileptogenic
`of penicillin
`lead to Paroxysmal Depolarization Shifts PDS The PDSs are charac
`and repetitive
`
`terized by abnormally
`
`large prolonged
`
`excitatory post
`
`synaptic
`
`potential
`
`and
`
`are believed
`
`to
`
`participate
`
`in
`
`the
`
`spread
`
`of
`
`electrical
`
`discharge
`
`during the seizure0
`
`The origins of EPRs are
`
`considered
`
`the key step in the epileptogeriesis
`
`These observations
`
`have
`
`led to
`
`six stage model
`
`for
`
`the gen
`
`eration of epileptic seizures
`
`the initiation of
`
`the EPR
`
`the gen
`
`eration of PDSs
`
`the recruitment of normal
`
`neurons
`
`the inter
`
`vention of control mechanisms that
`
`limit
`
`the spread of
`
`the epileptic
`
`discharges
`
`or promote selective
`
`routes of
`
`spread
`
`the establishment
`
`
`
`of satellite and independent
`
`epileptic
`
`foci
`
`and
`
`the
`
`engagement
`
`of
`
`the brain stem and of
`
`the spinal motor neuron pools.10
`
`COOH
`
`Both
`
`the
`
`generation
`
`of
`
`the
`
`EPA
`
`and the
`
`recruitment of
`
`normal
`
`neurons
`
`in
`
`the
`
`epileptic
`
`seizure
`
`have
`
`been
`
`extensively
`
`examined
`
`The EPR has
`
`sometimes been related
`
`to local deteriora
`
`tion
`
`of
`
`neurons
`
`by extraneuronal
`
`factors
`
`In
`
`1880
`
`Sommer
`
`observed
`
`an
`
`extensive
`
`loss of neural mass
`
`in
`
`the
`
`hippocampal
`
`area
`
`of one
`
`third of
`
`the
`
`epileptic
`
`patients
`
`examined
`
`after
`
`Shortly
`
`Alzheimer
`
`and Chaslin independently
`
`reported
`
`an
`
`associated
`
`abnor
`
`mal
`
`proliferation
`
`of
`
`glial
`
`cells
`
`in
`
`the
`
`same area7
`
`Gliosis has
`
`been
`
`related to seizures
`
`in three ways
`
`First
`
`this process may be
`
`biological
`
`response
`
`to
`
`decrease in neural matter.7
`
`Second ab
`
`normal
`
`proliferation of
`
`glial
`
`cells may mechanically
`
`irritate
`
`the
`
`neurons
`
`and
`
`initiate
`
`the
`
`EPA-mediated
`
`processes7
`
`Third glial
`
`cells are known
`
`to participate
`
`in the regulation
`
`of
`
`the
`
`potassium ion
`
`concentration
`
`in
`
`the
`
`brain
`
`and
`
`in
`
`the metabolism of
`
`amino
`
`
`
`r...4
`
`butyric acid
`
`These
`
`substances may
`
`influence
`
`the
`
`seizure
`
`processes.1
`
`Finally
`
`De Moor and Westrum noticed
`
`dendritic
`
`alterations
`
`adjacent
`
`to
`
`epileptic
`
`foci
`
`in
`
`human
`
`cortices
`
`and
`
`expenmentally
`
`generated
`
`epileptic centers
`
`respectively.712
`
`H2N ii
`
`Other
`
`factors which may be
`
`responsible
`
`for
`
`the generation
`
`of
`
`the
`
`EPR
`
`are
`
`associated with
`
`the blood-brain
`
`barrier
`
`Scheibel7
`
`observed
`
`that
`
`neurons
`
`in epileptic
`
`foci were
`
`often
`
`altered
`
`in
`
`regions
`
`nearby
`
`damaged
`
`capillaries
`
`He
`
`attributed
`
`the
`
`generation
`
`to
`
`factors
`
`of
`
`epileptic
`
`neurons
`
`exogenic
`
`such as
`
`viruses
`
`and
`
`toxins
`
`Despite
`
`these
`
`important
`
`initiation
`
`processes
`
`the majority of
`
`researchers
`
`consider metabolic
`
`disorders
`
`existent
`
`in
`
`the
`
`epileptic
`
`patient
`
`to be the primary cause of
`
`the disease.3i0
`
`Most sub
`
`stances
`
`involved
`
`in the
`
`normal
`
`neuronal
`
`activity
`
`as well as
`
`their
`
`associated metabolic
`
`cycles
`
`have
`
`been claimed
`
`to participate
`
`in
`
`the
`
`EPR
`
`generation1013
`
`Extensive
`
`which
`
`demonstrate
`
`the
`
`involvement
`
`evidence
`experimental
`of potassium ion81045
`
`exists
`
`both
`
`and
`
`the neuronal
`
`sodium-potassium pump1 in the
`
`first step of
`
`the
`
`
`
`seizure
`
`Other ions
`
`i.e C1 Ca NH4 may also be involved
`
`in
`
`abnormal membrane
`
`depolarization
`
`processes.8
`
`Disorders
`
`in
`
`the metabolic
`
`cycles
`
`of
`
`all
`
`the substances
`
`regulating
`
`the concen
`
`tration
`
`and
`
`the transport
`
`of
`
`these
`
`ions across
`
`the membrane
`
`of
`
`the neuron as well as structural
`
`disorders
`
`in the
`
`neuron mem
`
`brane can
`
`ultimately
`
`be responsible
`
`for
`
`the EPR generation
`
`Several
`
`explanations
`
`have
`
`been
`
`offered
`
`for
`
`the mechanism
`
`involved
`
`in
`
`the
`
`recruitment
`
`of
`
`normal neurons
`
`in
`
`the
`
`seizure
`
`Variations
`
`in
`
`the
`
`proteinic
`
`constitution
`
`of
`
`the
`
`synapses
`
`have
`
`been
`
`invoked
`
`to
`
`explain
`
`the
`
`propagation
`
`of
`
`the
`
`epileptic
`
`discharge
`
`by
`
`selective
`
`neuronal
`
`circuits
`
`The
`
`same
`
`explanation
`
`has
`
`been
`
`for
`
`the
`
`creation
`
`of
`
`foci
`
`suggested
`
`secondary
`
`epileptic
`
`Exten
`
`sive documentation
`
`does exist
`
`in support
`
`of various
`
`other
`
`phenom
`
`ena
`
`These
`
`include
`
`the enhancement
`
`of
`
`the excitatory
`
`neuro
`
`transmissions
`
`induced
`
`by
`
`substances
`
`such
`
`as
`
`acetyicholine
`
`aspartic
`
`acid
`
`glutamic
`
`acid
`
`5J
`
`and
`
`some
`
`neuropeptides
`
`as
`
`well
`
`as
`
`the
`
`decrease
`
`in
`
`inhibitory
`
`regulation
`
`promoted
`
`by
`
`substances
`
`such
`
`as
`
`and
`
`aminobutyric
`
`dopamine
`norepinephrine
`acid GABA Z.8 7-20
`
`serotonin
`
`Finally
`
`transient
`
`modifications
`
`of
`
`the membrane
`
`of
`
`the normal neuron
`
`and anomalies
`
`in
`
`the
`
`dendritic
`
`and
`
`axon
`
`structures
`
`are
`
`also
`
`believed
`
`to
`
`participate
`
`in
`
`the epileptic
`
`discharge
`
`propagation
`
`xx Symptomatology
`
`and Classification
`
`of Epileptic Seizures
`
`The
`
`part of
`
`the brain affected by the epileptic discharges
`
`has
`
`.1
`
`L..
`
`_________
`
`
`
`.1
`
`CH3
`IcI-
`
`CH33
`
`HO.yAOH
`
`HOJoH
`
`HO
`
`NH2
`
`OH
`
`NH2
`
`OH
`
`OH
`
`HO
`
`Lb..
`
`Li
`
`
`
`direct
`
`bearing
`
`on
`
`the
`
`clinical manisfestation
`
`of
`
`the disease
`
`In
`
`some cases careful monitoring
`
`of
`
`the patient
`
`can permit
`
`the physi
`
`cian
`
`to follow the
`
`spread
`
`of
`
`the abnormal
`
`brain electrical
`
`activity
`
`The
`
`observed
`
`clinical
`
`symptoms serve
`
`as
`
`basis
`
`for
`
`the currently
`
`employed
`
`classifications
`
`of
`
`the
`
`various
`
`seizure
`
`states
`
`The first widely accepted classification
`
`of
`
`the epileptic
`
`seizures
`
`Table
`
`was
`
`established
`
`by the
`
`International
`
`League
`
`Against
`
`Epilepsy
`
`in
`
`1969.1122
`
`This
`
`classification
`
`attempted
`
`to correlate
`
`the
`
`symptoms
`
`and
`
`electroencephalographic
`
`EEG data
`
`to the
`
`anatomic
`
`substrate the etiology and
`
`the age
`
`of
`
`the patient
`
`This
`
`system difterentiated
`
`seizures
`
`which
`
`had
`
`focal
`
`onset
`
`and
`
`evolved
`
`into
`
`generalized
`
`seizures
`
`from
`
`those
`
`which
`
`are
`
`generalized
`
`from the
`
`beginning.1
`
`revised
`
`classification
`
`Table
`
`appeared in 1981
`
`This
`
`new classification
`
`was
`
`fostered
`
`by
`
`the
`
`development
`
`of
`
`better methods
`
`to
`
`analyze
`
`the
`
`seizures
`
`i.e
`
`telemetered
`
`EEG videotaping
`
`The major
`
`changes
`
`incorporated
`
`in
`
`the
`
`new system were
`
`the exclusive
`
`use
`
`of
`
`the
`
`clinical
`
`and
`
`electroencephalographic
`
`data
`
`to
`
`determine
`
`the
`
`seizure
`
`type
`
`and
`
`the
`
`restructuring
`
`of
`
`the
`
`partial
`
`seizures
`
`into
`
`simple
`
`partial
`
`seizures and
`
`complex
`
`partial
`
`seizures depending
`
`on whether
`
`or
`
`not
`
`consciousness
`
`is
`
`altered
`
`at
`
`the
`
`onset
`
`or
`
`in
`
`the
`
`further
`
`evolution
`
`of
`
`the seizure
`
`Although1
`
`clinical
`
`discussion
`
`of
`
`the vanous
`
`types
`
`of
`
`seizures
`
`is beyond
`
`the scope
`
`of
`
`this
`
`thesis
`
`btief
`
`review of
`
`the
`
`major
`
`forms of
`
`the disease follows
`
`iL.
`
`
`
`ble
`
`The
`
`International Classification of Epileptic Seizures.1
`
`Partial
`
`seizures seizures beginning
`locafly
`seizures with elementary symptomatology generally
`Partial
`impairment of consciousness
`without
`With motor symptoms includes Jacksonian seizures
`With special sensory or somatosensory symptoms
`With automatic symptoms
`Compound
`forms
`Partial seizures with complex -symptomatology
`with impairment of consciousness temporal
`motor seizures
`With impairment of consciousness
`With cognitive
`symptomatology
`With affective symptomatology
`With psychosensory symptomatology
`With psychomotor sympto matology automatisms
`Compound forms
`seizures secondarily generalized
`Partial
`
`generally
`lobe or psycho-
`
`only
`
`ii
`
`iii
`
`iv
`
`Generalized seizures bilaterally symmetrical and without
`onset
`Absence petit mal
`Bilateral massive epileptic myoclonus
`Infantile spasms
`Clonic
`features
`
`local
`
`Tonic features
`
`Tonic-clonic
`
`seizures grand ma
`
`Atonic seizures
`
`Akinetic seizures
`
`Unilateral
`
`seizures or predominately
`
`Unclassified
`
`epileptic seizures due to incomplete data
`
`
`
`ble
`
`The Revised Classification of Epileptic Seizures.1
`
`seizures consciousness
`Simple partial
`With motor signs
`Focal motor without march
`Focal motor with march Jacksonian
`Versive
`
`not
`
`impaired
`
`Postural
`Phonatory vocalization or arrest of speech
`symptoms
`With
`somatosensory
`or special-sensory
`hallucinations e.g tingling light
`flashes buzzing
`Somatosensory
`Visual
`
`simple
`
`Auditory
`
`Olfactory
`
`function
`
`Gustatory
`Vertiginous
`symptQms or signs
`With automatic
`With psychic symptoms disturbance of higher cortical
`Dysphasic
`Dysnesmic e.g deja vu
`Cognitive e.g forced thinking
`Affective e.g fear anger
`Illusions e.g macropsia
`hallucinations e.g music scenes
`Structured
`Complex partial seizures generally with
`impairment of conscious-
`sometimes begin with simple symptomatology
`ness may
`followed by impairment of consciousness
`Simple partial onset
`features A-D and
`With
`simple
`impaired
`consciousness
`With automatisms
`With impairment of consciousness
`With impairment of
`consciousness
`With automatisms
`
`partial
`
`at onset
`
`only
`
`ii
`
`iii
`
`Partial
`
`to
`
`seizures
`evolving
`generalized
`seizures GTC with partial or focal onset
`evolving to GTC
`Simple partial seizures
`Complex partial seizures Ii
`to GTC
`evolving
`Simple partial seizures evolving
`to complex
`evolving to GTC
`
`partial
`
`seizures
`
`tonic-clonic GTC
`
`
`
`__
`
`10
`
`Ible
`
`cont
`
`iv
`
`VI
`
`Generalized seizures bilaterally symmetrical
`onset
`Absence petit mal
`Bilateral massive
`epileptic myoclonus
`
`and without
`
`local
`
`Infantile spasms
`Clonic features
`Tonic
`features
`seizures grand mat
`Tonic-clonic
`Atonic seizures
`seizures or predominately
`epileptic seizures due to incomplete data
`Unclassified
`
`Unilateral
`
`
`
`Simple partial
`
`seizures affect
`
`any part of
`
`the body depend-
`
`ing
`
`on the origin
`
`of
`
`the discharge
`
`in
`
`the motor strip
`
`The clini
`
`cal observations
`
`are characterized
`
`by
`
`tonic
`
`contraction
`
`of
`
`the activa
`
`ted muscles
`
`followed
`
`by
`
`clonus
`
`Generally
`
`one muscle
`
`or
`
`group
`
`of muscles are
`
`involved
`
`in
`
`the seizure resulting
`
`in
`
`invol
`
`untary movements
`
`involuntary
`
`actions
`
`i.e.
`
`vocalization
`
`or posture
`
`change
`
`The
`
`step
`
`by
`
`step
`
`spread
`
`of
`
`the
`
`electrical disorder
`
`from
`
`strictly
`
`focal
`
`to adjacent
`
`areas
`
`produce sequential
`
`involvement
`
`body
`
`parts
`
`and
`
`is
`
`referred to
`
`as
`
`the
`
`epileptic
`
`march
`
`of
`
`or
`
`Jacksonian
`
`seizure.1
`
`These muscular disorders find
`
`their origin
`
`in the
`
`part of
`
`the cortex
`
`responsible
`
`for motor activity
`
`Likewise
`
`or
`
`in
`
`of
`
`the
`
`epileptic
`
`discharges
`
`originating
`
`spreading
`
`the part
`
`cortex
`
`responsible
`
`for automatic
`
`functions
`
`result
`
`in manisfestations
`
`such as
`
`vomiting
`
`incontinence
`
`pupil
`
`dilatation
`
`and
`
`pallor.1
`
`Involvement
`
`of
`
`the
`
`cortex area
`
`subversing
`
`somatosensory and
`
`psychic
`
`functions
`
`lead to
`
`additional
`
`seizure manifestations within
`
`this general
`
`class
`
`of
`
`seizures Table
`
`In
`
`all
`
`instances
`
`partial
`
`seizures are not
`
`associated with consciousness
`
`impairment
`
`Complex
`
`partial
`
`seizures
`
`are
`
`characterized
`
`by
`
`partial
`
`seizure
`
`symptoms with
`
`accompanying
`
`impairment
`
`of consciousness
`
`This often
`
`results
`
`in automatisms
`
`masticatory
`
`and
`
`sometimes
`
`results
`
`i.e verbal ambulatory
`confusion.1 23
`
`in
`
`gestural
`
`This
`
`disease
`
`state
`
`is
`
`always
`
`associated
`
`with
`
`various
`
`degrees
`
`of
`
`amnesia.5
`
`Generalized seizures which
`
`are
`
`non-convulsive
`
`are
`
`referred
`
`
`
`12
`
`to
`
`as
`
`absence
`
`petit ma seizures
`
`Absence
`
`seizures
`
`affect
`
`children
`
`before
`
`puberty
`
`and
`
`are characterized
`
`by
`
`frequent 5- 100
`
`per day
`
`attacks
`
`of
`
`impaired
`
`consciousness
`
`lasting
`
`usually less
`
`than
`
`20 seconds
`
`Interruption
`
`of
`
`ongoing
`
`activities
`
`staring occa
`
`sional
`
`eyes movements
`
`arm jerks
`
`and modification
`
`of
`
`the
`
`postural
`
`tone
`
`are manisfestations
`
`of
`
`this type
`
`of
`
`seizure
`
`The
`
`associated
`
`EEG is
`
`characterized
`
`by
`
`regular
`
`three per second
`
`spike
`
`and wave
`
`pattern
`
`The
`
`classification
`
`of
`
`generalized
`
`seizures
`
`involving
`
`con
`
`vulsions
`
`has
`
`been
`
`subdivided
`
`according
`
`to
`
`the characteristics
`
`of
`
`the
`
`convulsive
`
`episodes
`
`Bilateral
`
`massive
`
`epileptic myoclonus
`
`and
`
`infantile
`
`spasms Wests
`
`syndrome
`
`are manisfested
`
`by
`
`sudden
`
`contractions
`
`of major muscle groups
`
`The latter
`
`seizure
`
`type occur
`
`before
`
`the
`
`involves
`
`age of
`
`four
`
`and
`
`legs
`
`arms
`
`and
`
`trunk
`
`muscles
`
`It
`
`is
`
`often
`
`related
`
`to phenylketonuria
`
`Iipidosis
`
`and
`
`the
`
`metabolism
`
`of
`
`piridoxine
`
`The EEG
`
`shows
`
`high vtage
`
`slow
`
`waves
`
`and
`
`spikes
`
`Both
`
`of
`
`these seizure types
`
`involve
`
`the
`
`right
`
`and
`
`left
`
`brains.1
`
`Clonic
`
`seizures
`
`occur
`
`especially
`
`in
`
`childhood
`
`and are manisfested
`
`by
`
`succession
`
`of
`
`shock-like
`
`spasms affect
`
`ing one or both
`
`sides of
`
`the body and
`
`are
`
`associated
`
`with con-
`
`sciousness
`
`impairment
`
`Tonic
`
`seizures
`
`are characterized
`
`by
`
`tonic
`
`contractions
`
`of
`
`long
`
`duration
`
`up to one minute of
`
`the
`
`trunkal
`
`and
`
`limbs musculatures
`
`and
`
`are
`
`associated with
`
`autonomic activ
`
`high
`
`voltage
`
`activity
`
`Tonic-clonic
`
`seizures
`
`ity
`
`The EEG shows
`grand ma are
`
`succession
`
`of
`
`tonic
`
`and
`
`clonic
`
`episodes
`
`with
`
`
`
`13
`
`loss
`
`of
`
`consciousness
`
`and
`
`autonomic
`
`hyperactivity
`
`This
`
`form of
`
`epilepsy
`
`can
`
`occur
`
`in
`
`both
`
`children
`
`and adults
`
`Grand mal
`
`is
`
`the most
`
`common
`
`type
`
`of epilepsy
`
`and
`
`the most disrupting
`
`in
`
`the
`
`life
`
`of
`
`the
`
`patient
`
`The
`
`chronicity
`
`of
`
`the
`
`seizures
`
`varies
`
`from one
`
`or more
`
`day
`
`to
`
`intervals
`
`of months
`
`between the
`
`seizure
`
`episodes.1
`
`xii
`
`Evaluation of Anticonvulsant Agents
`
`Many procedures
`
`have
`
`been designed
`
`and
`
`evaluated
`
`for the
`
`screening
`
`of
`
`potential
`
`anticonvulsant
`
`drugs.24
`
`Current
`
`protocols
`
`can
`
`be
`
`divided
`
`into four
`
`general
`
`categories
`
`the employment
`
`of
`
`chemical
`
`convulsant
`
`to induce the
`
`artifical
`
`seizures in
`
`the
`
`use of electncally
`
`induced
`
`seizures
`
`in animals
`
`animals
`
`the em
`
`Ii
`
`ployment
`
`of
`
`genetically
`
`predisposed
`
`animal
`
`strains
`
`the
`
`use
`
`of nervous
`
`tissues
`
`in
`
`in i1rQ expenments.7
`
`Many
`
`chemical
`
`convulsants
`
`have
`
`been utilized
`
`to generate
`
`artificial
`
`seizures.172425
`
`The most widely
`
`used chemical
`
`convul
`
`sants are
`tylenetetrazol Metrazol 12
`
`strychnine
`
`picrotoxin
`
`bicuculline it
`
`and
`
`pen-
`
`All
`
`these subtances
`
`are subcutan
`
`eously
`
`injected
`
`in
`
`the
`
`test animals after the
`
`administration of
`
`the
`
`compound
`
`to be
`
`evaluated
`
`for anticonvulsant
`
`properties.26
`
`The
`
`augmentation
`
`of
`
`the
`
`seizure
`
`threshold
`
`reveals
`
`the
`
`anticonvul
`
`sant
`
`activity
`
`of
`
`the
`
`drug
`
`The
`
`pentylenetetrazol
`
`scMet
`
`seizure
`
`threshold test2729
`
`is
`
`of
`
`particular
`
`interest
`
`in
`
`the evaluation
`
`of
`
`new
`
`compounds
`
`It
`
`is widely
`
`recognized
`
`that
`
`substances
`
`active
`
`
`
`14
`
`\L2.N_cH
`
`o._j
`
`11
`
`cr
`
`12
`
`NNR
`
`13
`
`R1 Ph R2Ph1 R3
`R1-Ph R2EtR3Me
`RPhI R2HR3Et
`
`
`
`15
`
`in
`
`this
`
`test
`
`are
`
`likely
`
`to
`
`be effective
`
`in
`
`the treatment
`of petit
`are em
`
`mal
`
`seizures provided
`
`threshold doses of pentylenetetrazol
`
`ployed to produce clonic seizures
`
`The use
`
`of
`
`electrically
`
`induced
`
`seizures was introduced
`
`in
`
`the mid-i 800s
`
`after
`
`the
`
`pioneering
`
`studies
`
`of Fritsch Hitzig and
`
`Albertoni.26
`
`The
`
`systematic
`
`use
`
`of
`
`electrically
`
`induced
`
`seizures in
`
`cats
`
`eventually
`
`led
`
`Putnam
`
`and Merntt3
`
`to
`
`discover
`
`the
`
`anticonvulsant
`
`Dilantin j.
`
`properties
`
`of
`
`55-diphenylhydantoin
`
`phenytoin
`
`This medicinal
`
`agent
`
`is
`
`the most extensively
`
`used
`
`drug today for
`
`the
`
`treatment of grand mal epilepsy
`
`Subsequently
`
`Goodman
`
`and his
`
`colleagues
`
`standardized the
`
`technique
`
`which
`
`is
`
`now named
`
`the Maximal Electroshock
`
`Seizure MES test.272931
`
`This
`
`test
`
`is
`
`believed
`
`to
`
`identify
`
`substances
`
`that will
`
`be useful
`
`the treatment
`
`of partial
`
`tonic-clonic
`
`seizures.3
`
`in
`
`In
`
`and generalized
`
`this
`
`technique
`
`60-cycle
`
`alternating
`
`current
`
`is
`
`applied
`
`for
`
`0.1
`
`or 0.3
`
`seconds
`
`to mice and
`
`rats
`
`by means
`
`of
`
`corneal
`
`electrodes
`
`Many
`
`been
`
`other
`
`useful
`
`electrically
`described.24272931 32
`
`induced
`
`seizure
`
`tests
`
`have
`
`also
`
`More
`
`recently
`
`kindling
`
`procedures
`
`have
`
`been
`
`introduced
`
`in
`
`the
`
`hopes
`
`of
`
`identifying
`
`new
`
`drugs
`
`specific
`
`for partial
`
`seizures.7
`
`The
`
`kindling
`
`process
`
`refers
`
`to
`
`an experimental
`
`protocol
`
`where subthreshold
`
`stimuli
`
`are
`
`repeat
`
`edly
`
`applied
`
`to
`
`the
`
`animal
`
`until
`
`they
`
`become
`
`convulsant stimuli
`
`This method
`
`requires the implantation
`
`of electrodes
`
`in the brain
`
`area where
`
`the
`
`epileptic
`
`discharge
`
`is
`
`to be generated
`
`Genetically
`
`predisposed
`
`animal
`
`strains have
`
`been
`
`employed
`
`
`
`16
`
`in
`
`the anticonvulsant
`
`testing
`
`of new substances
`
`Among
`
`these
`
`three
`
`species
`
`have
`
`found
`
`extensive
`
`use
`
`They
`
`are
`
`the DBA/2
`
`Dilute
`
`Brown Agouti
`
`strain
`
`of
`
`house mouse
`
`in which
`
`seizures
`
`are
`
`elicited
`
`by audiogenic
`
`stimuli
`
`such
`
`as
`
`door bell33
`
`the
`
`Wistar
`
`strain of
`
`rat
`
`in which
`
`seizures
`
`appear
`
`to
`
`be similar to
`
`petit mal
`
`and
`
`the
`
`baboon Papio papio
`
`in which
`
`responses to
`
`anticonvulsant
`
`drugs
`
`are similar
`
`to that
`
`observed
`
`in human.243536
`
`In
`
`this last strain
`
`of
`
`animal
`
`the seizure
`
`is
`
`induced
`
`by flicker
`
`ing light
`
`Various
`
`in
`
`vitro
`
`test systems
`
`have been developed for
`
`the
`
`evaluation
`
`of
`
`anticonvulsant
`
`properties
`
`of drug
`
`candidates.17
`
`These
`
`procedures
`
`were
`
`originally
`
`developed
`
`to
`
`study
`
`the
`
`biogenesis
`
`of
`
`the
`
`epilepsies.24
`
`Hippocampal
`
`slices
`
`of
`
`rats
`
`and
`
`well
`
`cultures
`
`guinea-pigs
`
`as
`
`as
`
`neuronal
`
`have
`
`been
`
`employed
`
`in
`
`the experimental
`
`protocols
`
`In
`
`the first case
`
`burst
`
`firing
`
`are
`
`generated
`
`by
`
`altering
`
`the
`
`extracellular
`
`ionic
`
`concentration
`
`or by
`
`the
`
`application
`
`of
`
`convulsant
`
`agents
`
`such
`
`as
`
`bicuculline
`
`or
`
`penicillin
`
`In
`
`the
`
`second
`
`case
`
`intracellular
`
`electrodes
`
`are used
`
`to deliver
`
`current
`
`pulse
`
`that
`
`generates
`
`epileptic
`
`activity
`
`In
`
`these tests
`
`the
`
`anticonvulsant
`
`properties
`
`the
`
`of
`
`the
`
`substances
`
`are
`
`determined by
`
`their ability
`
`to limit
`
`the
`
`spread
`
`of
`
`the
`
`epileptic
`
`electrical
`
`phenomena
`
`to
`
`non-stimulated
`
`areas.17
`
`None
`
`of
`
`the currently
`
`available
`
`test
`
`procedures
`
`indepen
`
`dently provides
`
`definitive method
`
`for
`
`the
`
`recognition
`
`of anti
`
`convulsant
`
`drugs
`
`Each
`
`procedure
`
`can
`
`give
`
`false-positive
`
`and
`
`
`
`17
`
`false-negative
`
`responses.1726
`
`Meidrum
`
`has
`
`urged
`
`the
`
`use
`
`of
`
`as many
`
`tests
`
`as
`
`possible
`
`in order
`
`to increase
`
`the chance
`
`of
`
`identifying
`
`new antiepileptic
`
`drugs.17
`
`In
`
`addition
`
`to these
`
`pro
`
`tocols
`
`the
`
`potential
`
`toxicty of
`
`new drugs must also
`
`be evalu
`
`ated
`
`and
`
`several
`
`general36
`
`and
`
`specific26
`
`tests
`
`have
`
`been
`
`described
`
`Of
`
`and
`
`the Horizontal
`
`are
`
`the
`
`rotarod
`
`ataxia
`
`the
`
`neurotox
`
`common
`these the most
`screen HS tests which evaluate
`in mice
`
`icity
`
`of
`
`test
`
`substances
`
`In
`
`the first
`
`of
`
`these
`
`tests
`
`the
`
`ability
`
`of
`
`the
`
`animal
`
`to maintain
`
`its
`
`equilibrium on
`
`rotating
`
`rpm knurled
`
`rod for more
`
`than
`
`one minute
`
`is determined
`
`after
`
`the
`
`administration
`
`of
`
`In the horizon
`
`intraperitoneal
`
`the drug 29a
`
`tal
`
`screen
`
`test
`
`the animal
`
`is
`
`placed on
`
`top of
`
`square 13
`
`13
`
`cm wire
`
`screen mounted
`
`on
`
`rod
`
`and
`
`the
`
`ability
`
`of animal
`
`to
`
`return
`
`on
`
`top
`
`of
`
`the
`
`screen
`
`when
`
`the
`
`rod
`
`is
`
`rotated 1800
`
`is
`
`determirled.29b
`
`Recently
`
`the
`
`U.S
`
`National
`
`Institute
`
`of Neurological
`
`and
`
`Communicative
`
`Disorders
`
`ileptic Drug Development
`
`and Stroke NINCDS
`Program ADD established
`
`through
`
`the Antiep
`
`fixed Se
`
`quence
`
`for
`
`the
`
`preclinical
`
`evaluation
`
`of
`
`novel
`
`anticonvulsant
`
`agents
`
`This
`
`protocol
`
`is given in Table 317
`
`iv Antiepileptic
`The first
`
`Drugs
`
`two drugs widely
`
`used for
`
`the treatment
`
`of
`
`epilepsy
`
`were
`
`potassium bromide
`
`iA1 introduced
`
`in 1857
`
`by
`
`Locock
`
`and
`
`phenobarbital
`
`Luminal
`
`introduced
`
`in 1912
`
`by
`
`
`
`Table
`
`Phase
`
`Phase
`
`Phase
`
`Phase
`
`Phase
`
`18
`
`Sequential
`
`Screening
`Program.17
`
`Test Phases
`
`Project
`
`of
`
`Utilized
`for
`the Antiepileptic
`
`the
`
`Anticonvulsant
`
`Drug
`
`Development
`
`indentification
`
`pentylenetetrazol
`
`to determine the level of activity
`Anticonvulsant
`to inactive 300 mg/kg mice i.p
`100 mg/kg
`Maximal electro-shock MES test
`seizure spread
`scMet
`Subcutaneous
`testseizure
`pentylenetetrazol
`threshold
`Rotarod ataxia testneurotoxicity
`Anticonvulsant
`to determine the level of activ
`quantification
`the ED50 TD50 and
`protective index TD50/ED50
`ity at
`mice i.p
`electro-shock MES testseizure spread
`Maximal
`scMet
`Subcutaneous
`testseizure
`threshold
`Rotarod ataxia testneurotoxicity
`Toxicity profile to assess general behaviour and selected
`toxic doses mice i.p
`pharmacologic
`response
`at
`lethal dose LD50
`Median
`Median hypnotic dose HD50
`to measure
`Anticonvulsant
`quantification
`route of a
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