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Kishan singh

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screening of anti epileptic

screening of anti epileptic

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  • 1. “SCREENING OF ANTIEPILEPTICS” Kishan Singh M.pharm.(pharmacology) GLAIPR 1
  • 2. Definitions:- It is a Chronic medical condition characterized by two or more unprovoked seizures. It is not a disease, it is a syndrome What is the difference between seizure & epilepsy ? 2
  • 3.  Seizure:  The clinical manifestations (signs and symptoms) of excessive and hyper synchronous, usually self limited, activity of neurons in the cerebral cortex. Epilepsy:  Epilepsy is a broad term for a variety of brain disorders characterized by seizures, or convulsions. Epilepsy can result from a direct injury to the brain at birth or from a metabolic disturbance in the brain at any time later in life. 3
  • 4. Seizures A seizure is a transient alteration of behavior due to abnormal synchronous electrical activity in the brain A seizure can be defined as abnormal, uncontrolled electrical activity in brain cells. Nerve cells transmit signals from the brain in two ways by 1. altering the concentrations of salts (sodium, potassium calcium,) within the cell 4
  • 5. 2.Releasing chemicals called neurotransmitters (gamma aminobutyric acid). The change in salt concentration conducts the impulse from one end of the nerve cell to the other.EpilepsyEpilepsy is a chronic neurological conditioncharacterized by recurrent seizures that are causedby abnormal cerebral nerve cell activity. 5
  • 6. Types of seizure s(focal) Primary 6
  • 7. Treatment: Up to 80% of parts can expect partial or complete control of seizures with appropriate treatment. Antiepileptic drugs suppress but do not cure seizures Antiepileptic are indicated when there is two or more seizures occurred in short interval An initial therapeutic aim is to use only one drug monotherapy) 7
  • 8. TREATMENT OF SEIZURESSeizure disorder DrugsTonic-clonic(Grand mal) Carbamazepine orDrug of Choice Valproate or Phenytoin or Phenobarbital or TopiramteAlternatives: Lamotrigine (as adjunct or alone) Gabapentin (as adjunct)Partial (simple or complex) Carbamazepine or LamotrigineDrug of choice orTopiramte or Phenytoin or ValproateAlternatives: Phenobarbital Gabapentin (as adjunct ) Zonisamide
  • 9. Treatment cont,dAbsence ( petit mal) Valproate orDrug of choice EthosuximideAlternatives: Clonazepam LamotrigineMyoclonic, Atonic ValproateDrug of choiceAlternatives: ClonazepamFebrile Seizures Diazepam, rectal Diazepam ,i.v Valproate
  • 10. Mechanism of Action  Reducing electrical excitability of cell membranes, possibly through inhibition of sodium channel.  Enhancing GABA-mediated synaptic inhibition. This may be achieved by an enhanced pre- or post- synaptic action of GABA, by inhibiting GABA-transaminase, or by drugs with direct GABA-agonist properties. 10
  • 11. Mechanism of Action A few drugs appear to act by a third mechanism, namely inhibition of T-type calcium channels. Newer drugs act by other mechanism, yet to be elucidated. Drugs that block excitatory amino acid receptors are effective in animal models, but not yet developed for clinical use. 11
  • 12. SCREENING METHODS  IN VITRO METHOD  IN VIVO METHOD 12
  • 13. IN VITRO METHODS1. Hippocampal slices2. Electrical recording from isolated brain cells 13
  • 14. IN VIVO METHODS1. ELECTRICALLY INDUCED SEIZURE2. CHEMICALLY INDUCED CONVULSION3. SEIZURES INDUCED BY FOCAL LESIONS4. OTHERS 14
  • 15. HIPPOCAMPAL SLICES Procedure and Evaluation:- Choose Rodent decapitated & hippocampus is dissected 0.5mm Preincubate for 2 hr thickness slices Slices are at 28c warm saline are made transferred in with 95%O2 &5% Perspex chamber CO2Intracellular recording frompyramidal neuron in the slice Drug are added in Record the shockare done by passing saline medium induce neuronsmicropipettes under firingmicroscope 15
  • 16. ADVANTAGES mechanical stable Useful model for studying the neurophysiologic mechanisms of convulsant and antiepileptic drugs For screening of antiepileptic drugs 16
  • 17. ELECTRICAL RECORDING FROMISOLATED BRAIN CELLS Procedure :- Put in bath Patch pipettesTaken isolated neuron are filled with containing salts at 7.3 pH same solution recording of capacitative currents Drug are added is done ,at room temp.(21-24c) in bath solution 17
  • 18. Evaluation Effect of drug on capacitative component of current Ic is seen Ic = Cdv/dt Where C = specific membrane capacitance dv/dt rate of change of membrane potential Using this technique find out the sensitivity of calcium and potassium channels to neurotransmitters 18
  • 19. IN VIVO METHODElectrically induced seizuresThese are three types1. Threshold model2. Maximal electroshock seizures (MES)test3 . Focal electrical stimulation such as kindling Corneal electroshock kindling Kindling by stimulation of the other brain areas Chemically induced kindling 19
  • 20. Threshold modelProcedure and evaluation:-Male mice of 18-30g Corneal or ear electrode arein group of 8-10 are used to provide constant taken current at frequency of 50- 60/sec for 0.2 sec Threshold is Elevation of determined as a voltage threshold by test drug inducing hind limb is taken as measure of extension in 50% mice efficacyAdvantage: This test determine the ability of drug to alter the seizure threshold for tonic limb extension 20
  • 21. Maximal electroshock seizure (MES)TEST Electrical Electrode are moistened with stimulation is saline solution before applied by corneal application or ear electrode current Stimulation for Measures various phages: phage of mice 50mA&for rat 150mA tonic limb flexion for 1.5sec. followed and 250 voltage for mice & by tonic limb extension for 10 sec. 750 for rat 21
  • 22. EvaluationSuppression of tonic hind limb extension istaken as measure of efficacy in this test andanticonvulsant potency is determined bycalculation of ED5o for suppression of tonichind limb extension 22
  • 23. KINDLED RAT SEIZURE MODEL(epilepsy induces epilepsy)PROCEDURE:- Female sprague- Electrode is implanted Dawely rats of 270- in right amygdala for 400g are taken electrical stimulation Daily electrical stimulus of 400 – 500 µ A are applied During the daily electrically in following 5 stages ….. stimulation of amygdala, seizures develop which ,as classified by Racine 23
  • 24.  Class - 1 Immobility , eye closure Class- 2 Facial clonus and head nodding Class- 3 Facial clonus and head nodding & fore limb clonus Class- 4 Rearing, often accompanied by bilateral fore limb clonus Class-5 Rearing with loss of balance and falling accompanied and generalized clonic 24
  • 25. Evaluation :-Four different measure of drug efficacy are measured for kindling:- Seizure latency Seizure severity Seizure duration After discharge durationMerits:-The efficacy of drug against the process of epileptogenesis as well as against the fully kindled state can be measured 25
  • 26. Chemical induced convulsions1. Chemoconvulsionsants inducing generalized seizures after systemic administration :- e.g.pentylenetetrazol, picrotoxin, isonizid,pencillin, strychine,p ilocarpine,NMDA,DDT,methioninen ,sulfoxime bicculine2. Chemoconvulsant inducing focal seizure after central administration :- e.g.pencillin.,quinolinic acid, ptz 26
  • 27. METHODS OF CHEMICALLY INDUCED CONVULSIONS:-• Pentylentetrazol(PTZ) test:-Procedure:-8-10 mice are taken and 1% solution of PTZ are administered i.v. infusion Seizure are developed in following manner1. jerks(first twitch)2. Generalized clonic seizure with loss of lightening reflexes3. Maximal tonic clonic seizure 27
  • 28. SEIZURES INDUCED BY FOCAL LSIONS CORTICALLY IMPLANTED MODEL ALUMINIUM HYDROXIDE GEL MODEL 28
  • 29. GENETIC ANIMAL MODELS OF EPILEPSY Photosensitive baboons Seizure-prone mice strains Mongolian gerbils Miscellaneous genetically seizure-prone animals 29
  • 30. CONCLUSIONCharacteristics for ideal model:- Development of spontaneously occurring seizure Type of seizure similar to that seen in human epilepsy EEG correlates of epileptic like activity Age dependency in the onset of epilepsyAt present there is no models that satisfy all above criteria only genetic model come close to above criteria. 30
  • 31. Thank youThank you for your attention 31