animal models for screening of antiepileptic drugs &
TRANSCRIPT
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SCREENING OF ANTIEPILEPTIC DRUGS & THEIR RECENT ADVANCES
DR KAMAL OJAH
DEPT. OF PHARMACOLOGY
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Outlines :
Brief overview on epilepsy
Antiepileptics drugs
Methods of screening of antiepileptics
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Epilepsy : disorder of brain function characterized by a periodic and unpredictable occurrence of seizures.
Seizure : abnormal increase electrical activity in the brain.
Convulsion : major motor manifestations of a seizure(rhythmic jerking of the limbs).
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Pathophysiology of epilepsy:
High frequency discharge of impulse by interconnected cerebral neurons.
Starts locally then spread.Enhancement of excitatory
transmission.Reduction of inhibitory transmission.
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Causes of epilepsy :
Neurological diseasesMedical trauma as stroke InfectionHead injuryNeoplasm of brain hereditary
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Types of epilepsy: Partial: involves small area brain , no loss of
consciousness.e.g. simple, complex. Generalised : spread over larger area of
brain,e.g. tonic-clonic, absence seizure,status epilepticus.
Secondarily generalised : generalised epilepsy that originates from partial event.
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Screening methods for antiepileptics
Principle :
The ability of antiepileptics drug to partially or completely antagonize seizure induced either electrically or chemically.
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Pharmacological screening:
involves sequential testing of drugs in
isolated organs followed by tests in
whole animals, mostly rats & mice but
also in higher animals if indicated.
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Animal model:
Is a living animal used during the
research & investigation of human
disease for the purpose of better
understanding the disease without the
added risk of causing harm to an actual
human being.
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In vivo methods: a) Electrically induced seizures
Threshold models Maximal electroshock seizure(MES) test Psychomotor seizures model Focal electrical stimulation such as
kindling
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Threshold models: Determine ability of a drug to alter the seizure
threshold for tonic limb extension.
Procedure : Mice are used. Corneal or ear electrode are used . Electrical stimulation at frequency of 50-60/sec
& 50mA for 0.2 sec.
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Evaluation : Elevation of threshold by the test drug is taken as a measure of its efficacy.
Maximal electroshock seizure(MES) test:This model is useful for screening of drugs effective against primary & secondary generalised tonic clonic seizure.
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Procedure:
Step1: Weight the animal & mark properly. Divide animals into 3 groups. Stimulus given with ear electrode. Phases of convulsions are recorded in each
mouse. The drugs are injected.
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Step 2:
Group1: Isotonic saline
Group2 : Phenytoin sodium, 30 mg/kg i.p.
Group 3: Phenobarbitone sodium,15 mg/kg ip
Step 3: Supramaximal shock given after 1 hrRecord whether ‘THLE’ present/absent.
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The resultant seizure pass through the phases
Phase of tonic limb flexion for 1.5 sec
Phase of tonic limb extention for 10 sec
Clonic interval (variable)
Asphyxial death (sometimes)
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The animals are observed closely for 2min
Disappearence of THLE used as +ve criterion.
Calculate percentage protection
Percentage protection = no. of animals with
THLE absent / total no. animal × 100
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Evaluation :
Supression of tonic hind limb extension taken as a measure of efficacy.
Antiepiletic potency is determined by calculation of ED50 for THLE.
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Drugs like phenytoin,CBZ, phenobarbitone are effective in this test.
Psychomotor seizures model: Mice are subjected to unidirectional current
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Animal becomes stunned and shows automatism lasting for 15-20 sec.
drugs inhibiting the effect of current in this test are potentially useful in psychomotor seizures
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Kindled rat seizure model:
Kindling is a phenomenon whereby repeated administration of an initially subconvulsive electrical or chemical stimulus results in progressive intensification of seizure activity culminating in a generalised seizure.
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• The animals are given stimulation through an electrode implanted in right amygdala
• Duration ,amplitude & seizure stage are recorded.
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Seizure severity is graded into 5 stages Facial clonus & head nodding Immobility ,eye closure, sterotyping
sniffing. Facial clonus, head nodding& forelimb
clonus
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Rearing accompanied by B/L forelimb clonus
Rearing with loss of balance & falling accompanied by GTC.
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Rats are considered to be kindled on the
1st stimulation causing a stage 5 seizure
which is followed by atleast 2
consecutive stage5 seizure.
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Evaluation:
Animals are tested on the day before and after the test compound is given.
Test & control group are compared with 4 different measures.
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a) Seizure latency
b) Seizure severity
c) Seizure duration
d) After discharge duration
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Drug efficacy can be measured by determining separate ED 50 value for total suppression of
• GTC
• Focal seizure
• Amygdala after discharge
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Kindling is used as a model for human temporal lobe epilepsy.
Other methods of kindling
• Corneal electroshock kindling
• Chemically induced kindling by PTZ
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Chemical induced seizures :
i. Pentylenetetrazol(PTZ) induced seizures
ii. Picrotoxin induced seizures
iii. Bicuculine induced seizures
iv. Strychnine induced seizures
v. Isoniazide induced seizures
vi. 4-aminopyridine induced seizure.
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PTZ induced seizure:
PTZ is a CNS stimulant. It produces jerky
type of clonic convulsion in mice
superceded by tonic convulsions.
Act by antagonising the inhibitory
GABAergic transmission.
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Methods :
Animals : groups of 6-10 mice of either sex
Route of administration:
• Determine s.c. CD97
• 1% solution of PTZ , 80-100mg/kg in scruff of neck.
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3 distinct phases constitutes PTZ seizure sequence i,e,
• Myoclonic jerk
• Clonic jerk
• THLE
• Death
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Evaluation :
• First episode of clonic jerking last for 5 sec followed by loss of righting reflex.
• Efficacy measured by ED50 for suppression of clonic seizure.
• Ethosuximide, valproate are effective.
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Picrotoxin induced convulsion:
• Picrotoxin is a GABA antagonist and modifies chloride ion channel of GABA receptor complex.
• Dose : 3.5 mg /kg
• Route : s.c.
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Bicuculine tests :
• Bicuculine is a GABA antagonist
• Dose : 1mg/kg
• Route : iv
• Tonic cinvulsions appear in all treated rats within 30 secs of inj.
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4-Aminopyridine induced seizures:
• 4-aminopyridine is K+ channel antagonist
• Epileptiform activity is mediated by non NMDA type receptors.
• Dose : 13.3 mg /kg
• Route: s.c
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Genetic animal model for epilepsyTotterer Mice:• Homozygous (tg/tg) strain totterer mice are prone to spontaneous seizure.
• Develop both partial & absent seizure
• Two seizure type in one model
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Lethergic mice:• Homozygous(lh/lh)
• Model for absent seizure
DBA/2J Mice:• Audiogenic seizure susceptible mice
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GEPRs:
Seizures can be induced by various stimuli
• Sound
• Hyperthermia
• Chemical
• Electrical
Model for tonic-clonic convulsion
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Photosensitive baboons:
• Intermittent light stimulation leads to seizure.
• Model for tonic clonic seizure.
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Mongolian gebrils:
Seizure can be provoked by• Placing animal in new environment
• Bright light
• Vigorous shaking of cage
• Model for petitmal/myoclonous
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In Vitro methods:
• Hippocampal slices model
• Electric recording from isolated brain cells
• GABA receptor binding assays
• Excitatory aminoacid receptor binding assays.
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Disadvantages of in vitro study:
• Does not give any proper idea about PK-PD interaction of drugs in living animals.
• Not possible to study compensatory changes that occur in body when drug is given.
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Conclusion :Ideal model of epilepsy should show following characteristics
• Development of spontaneously occurring seizures
• Type of seizure similar to that seen in human epilepsy
• EEG correlates of epileptic like activity
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At present no models follows all criteria
Only genetic model come close to call ideal& resemble epilepsy in humans more closely than any other experimental model.
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Recent advances in antiepileptic drugs
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classical newer
• Phenytoin Lamotrigine
• Phenobarbital Felbamate
• Primidone Topiramate
• Carbamazipine Gabapentin
• Ethosuximide Tiagabine
• Valproate Vigabatrin
Oxycarbazepine
Levetiracetam
Fosphenytoin
Lacosamide
Classification of AEDs:
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Schematics of mechanism of action
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LAMOTRIGINE:
• Presently use as add-on therapy with valproic acid
• Supress rapid firing of neurons by inhibiting Na channels ,effective in partial seizures.
• Almost completely absorbed orally.
• T1/2 = 24 hrs
• Best safety record in pregnancy.
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Adverse effect:
• Dizziness
• Headache
• Diplopia
• Nausea
• Somnolence
• High rate of dematological reaction(SJD)
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TOPIRAMATE :
• Rapidly absorbed orally.
• T1/2= 20-30hrs, bioav. is ≥ 80%
• Block voltage dependant sod. Channels, also potentiates inhibitory effect of GABA, depresses excitatory action kainite on AMPA receptor.
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Adverse effects :
• Somnolence
• Fatigue
• Dizziness
• Cognitive slowing
• confusion
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FELBAMATE :
• Blocks glutamate NMDA receptors
• T1/2 is 20 hrs
• Effective in partial seizure
• Causes aplastic anaemia , hepatotoxicity.
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ZONISAMIDE :
• Sulfonamide derivative
• T1/2= 1-3 days
• Inactivation of Na channels
• Add on therapy in partial & GTCS
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Adverse effects:
• Drowsiness
• Cognitive impairment
• High incidence of renal stone
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VIGABATRIN :
• Absorption is rapid
• Bioav. is 60% , T1/2 = 4-7 hrs
• Increases inhibitory effects of GABA by
GABA transaminase.
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Adverse effect :
• Visual field defect
• Psychosis
• Depression
(limits its use.)
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TIAGABINE :
• 100% bioav., highly protein bound
• T1/2 = 5-8 hrs
• GABA uptake inhibitor
• Add on therapy in partial and GTCS.
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Adverse effect
• Dizziness
• Tremors
• Cognitive impairment
• Asthenia
• Skin rash
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GABAPENTIN :
• Structural analogue of GABA
• Increases activity of GABA or inhibits its reuptake.
• Not metabolized and excreted unchanged in urine.
• T1/2 = 5-7 hrs
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Adverse effect :
• Somnolence
• Dizziness
• Ataxia
• nystagmus
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LACOSAMIDE :
• Bio av. 100%
• Inhibit Na channels, CRMP-2.
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Adverse effect :
Headache
Nausea
dizziness
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LEVETIRACETAM:
• Piracetam derivative
• Binds selectively to SV2A protein of synaptic vesicles & glutamate & GABA release.
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Adverse effect :
• Dizziness
• Somnolence
• asthenia
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