{"id":379,"date":"2020-02-16T11:09:28","date_gmt":"2020-02-16T05:39:28","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=379"},"modified":"2020-02-16T11:09:28","modified_gmt":"2020-02-16T05:39:28","slug":"evaluation-of-anti-epileptic-drugs","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/evaluation-of-anti-epileptic-drugs\/","title":{"rendered":"Evaluation of anti-epileptic drugs"},"content":{"rendered":"\n<p><strong><em><u>Evaluation of anti-epileptic drugs:<\/u><\/em><\/strong><\/p>\n\n\n\n<p><strong>Seizure:<\/strong> Paroxysmal event due to abnormal, excessive, hyper synchronous discharges from an aggregate of central nervous system (CNS) neurons.<\/p>\n\n\n\n<p><strong>Epilepsy:<\/strong> Recurrent seizures due to chronic, underlying process, defined as two or more unprovoked seizures.<\/p>\n\n\n\n<p>Indian prevalence: 3.0-11.9 per 1,000 population<\/p>\n\n\n\n<p><strong><u>Mechanism of seizure initiation<\/u><\/strong><\/p>\n\n\n\n<p><strong>1. Initiation Phase<\/strong><\/p>\n\n\n\n<ul><li>&nbsp;<strong>High-frequency bursts of action potentials Long-lasting depolarization of neuronal membrane due to influx of extracellular calcium (Ca<sup>2+<\/sup>)Opening of voltage-dependent sodium (Na<sup>+<\/sup>) channelsInflux of Na<sup>+<\/sup> &amp; generation of repetitive action potentials<\/strong><ul><li><strong>Hyper synchronization<\/strong><ul><li>Increase in extracellular K<sup>+<\/sup>, which blunts hyperpolarization and depolarizes neighbouring neurons<\/li><\/ul><ul><li>Accumulation of Ca<sup>2+<\/sup> in presynaptic terminals leading to enhanced neurotransmitter release<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n<p>2.&nbsp; <strong>Propagation Phase<\/strong><\/p>\n\n\n\n<ul><li>Recruitment of sufficient number of neurons leads to loss of surrounding inhibition<\/li><li>Propagation of seizure activity into contiguous areas via local cortical connections<\/li><li>To distant areas via long commissural pathways such as the corpus callosum<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"292\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-45.png?w=480\" alt=\"\" class=\"wp-image-380\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-45.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-45-300x183.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"279\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-46.png?w=480\" alt=\"\" class=\"wp-image-381\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-46.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-46-300x174.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<ol type=\"1\"><li>Need for new drugs:<ol><li>1\/3<sup>rd<\/sup> patients don\u2019t respond to current medications.<\/li><\/ol><ol><li>1\/4<sup>th<\/sup> patients discontinue medications d\/t side effects.<\/li><\/ol><ol><li>Epileptic syndromes are resistant to current medications.<\/li><\/ol><\/li><\/ol>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"297\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-47.png?w=480\" alt=\"\" class=\"wp-image-382\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-47.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-47-300x186.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<ul><li>Hippocampal slices are used. Electrical activity of isolated rat neurons is recorded. Patch clamp technique is used.<\/li><li>Assay for GABAergic drugs: 3H GABA binding assay. Muscimol binding assay<\/li><li>Assay for excitatory aa receptor binding: Glycine binding assay, CPP binding assay, TCP binding assay<\/li><li>Advan: Less quantity of drug is required. Numerous drugs can be tested. First insight into the molecular mechanism of action<\/li><li>Disad: Drugs with novel MOA cannot be tested<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"303\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-48.png?w=480\" alt=\"\" class=\"wp-image-383\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-48.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-48-300x189.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<ul><li>In-vivo animal models<\/li><li>Electrical stimulation model<\/li><li>MES model (<strong>Maximal&nbsp; Electroshock Seizure)<\/strong>: Swiss albino mice or wistar rats are used. Electroconvulsiometer with corneal or ear electrodes are used.<\/li><li>Rat: 150 mA, 60 Hz, 2 sec. Mice: 50mA, 50 Hz, 2 secs<\/li><li>Phases: flexion, extension, clonus, at times death.<\/li><li>Endpoint: disappearance of THLE (Tonic hind limb extension)<\/li><li>Disadvan: Does not give idea of the MOA.<\/li><li>Threshold for MES: Determines the drugs ability to raise the threshold of MES. The test drug should raise the threshold by atleast 20%.<\/li><\/ul>\n\n\n\n<ul><li>Models for absence seizures<\/li><li>PTZ model <strong>(Pentylenetetrazol):<\/strong> PTZ decreases the recovery time of the post synaptic neurons of the spinal cord.<\/li><li>75 mg\/kg i.p.<\/li><li>Phases:<ul><li>Myoclonus : whole body twitch with Straub tail phenomenon<\/li><\/ul><ul><li>Clonus:&nbsp; Clonic spasms, stupor &amp; unusual positioning.<\/li><\/ul><ul><li>Tonic-clonic hind limb extension.<\/li><\/ul><ul><li>Death: in some animals.<\/li><\/ul><\/li><li>Endpoints:<ul><li>Abolition of both clonic and tonic seizures.<\/li><\/ul><ul><li>Time to onset of seizures<\/li><\/ul><\/li><li>Drawbacks: Anxiolytic drugs also have an effect<\/li><li>Bicuculline model: GABA receptor antagonist<\/li><li>INH model: Decreases synthesis of GABA<\/li><li>Strychnine model: Blocks the inhibitory effects of glycine.<ul><li>Animal : Swiss mice or rat<\/li><\/ul><ul><li>Dose : 2 mg\/kg, 30 min after test drug<\/li><\/ul><ul><li>Route: I.P.<\/li><\/ul><ul><li>Evaluation: Time for onset of tonic extensor convulsions.<\/li><\/ul><\/li><li>Picrotoxin- GABA antagonist, Endpoint: Time taken for the onset of seizure<\/li><li>Penicillin<ul><li>Dose: 300000 units\/kg of penicillin<\/li><\/ul><ul><li>Animal: cat, observed for 6-8 hrs after injection<\/li><\/ul><ul><li>Episodes of seizure:<ul><li>Arrested activity<\/li><\/ul><ul><li>Staring &amp; myoclonus,<\/li><\/ul><ul><li>Facial-oral twitching<\/li><\/ul><ul><li>Progression to generalized tonic clonic seizures<\/li><\/ul><\/li><\/ul><\/li><li>Modification: Rats can be used for the penicillin model of epilepsy.<\/li><li>This model is useful for screening of drugs useful in petit mal epilepsy. Ethosuximide and valproate are effective in this model.<\/li><\/ul>\n\n\n\n<ul><li><strong>Seizures induced by focal lesion<\/strong><\/li><li>Topical or intra-cerebral application of metals and chemicals can lead to focal seizures.<\/li><li>Cortically implanted metals: Cobalt, tungstic acid &amp; Aluminium Hydroxide Gel.<\/li><li>Aluminium hydroxide gel model: 4% Applied to the neocortex of monkey. 1-2 months after injection, spontaneous and recurrent seizures begin which persist for several months.<\/li><li>Hippocampal injections of chemicals: Kainic acid, topical pencillin, Tetanus toxin, Picrotoxin, Bicuculline, Strychnine, zinc.<\/li><\/ul>\n\n\n\n<ul><li><strong>Models of Status epilepticus<\/strong><\/li><li>Pilocarpine induced SE: 380-400 mg\/kg i.p. Systemic inflammation and damamge to the BBB.<\/li><li>Lithium-pilocarpine induced SE.<\/li><\/ul>\n\n\n\n<ul><li>&nbsp;Models of infantile spasms:<\/li><li>Pregnant SD rats are injected with Betamethsone (0.4mg\/kg IP) at 8 AM and 6PM on gestational day 15. Then after the pups are delivered \u00e0 NMDA is administered to them i.p. Betamethasone increases the sensitivity of the pup brain to NMDA.<\/li><li>Sequence of Seizures: Twisting movement of the tail. Arching. Loss of righting reflex and flexion spasms.<\/li><li>Only ACTH responds.<\/li><\/ul>\n\n\n\n<ul><li>Genetic models<\/li><li>Most of the animal models for screening of antiepileptic drugs are basically models of seizures rather than of epilepsy, which is a condition of chronically recurrent spontaneous seizures.<\/li><li>genetic animal models more closely approximate human epilepsy and give opportunity to study genetic and biochernical basis of epilepsy.<\/li><li><strong>Photosensitivity of the baboons:<\/strong> Intermittent light stimulation at 25 Hz. Seizure begins in eyelid, face then whole body.<\/li><li><strong>Seizure prone mice:<\/strong><ul><li>Audiogenic seizure susceptible mice-<\/li><\/ul><\/li><\/ul>\n\n\n\n<p>Between the ages of 2-4 weeks, these mice exhibit sound\u2014induced seizures, after which susceptibility gradually declines, such that by 8 weeks of age they are totally free of audiogenic seizures.<\/p>\n\n\n\n<p>Susceptible mice are exposed to sudden, loud sound which contains frequency components in the 12-16 kHz range. The seizure pattern involves a wild running phase, followed by clonic&nbsp; convulsions and a tonic extension ultimately leading to respiratory arrest (in about 60%) or full recovery.<\/p>\n\n\n\n<p>Anticonvulsant effect of drugs is evaluated by efficacy against clonic seizures. Audiogenic seizures can be prevented by phenytoin or phenobarbital or valproic acid. Audiogenic seizure susceptible mice are useful as sensitive gross screening model for potential anticonvulsant drugs.<\/p>\n\n\n\n<ul><li>E1 mice (seizure d\/t vestibular stimulation)<\/li><\/ul>\n\n\n\n<p>exhibit seizures in response to vestibular stimulation like tossing or spinning. manifestation of seizure include limb and face automatism like chewing and salivation. There may be secondary generalization to tonic\u2014clonic seizures. EEG recordings indicate onset of electrical discharge in deep limbic structures. Thus, these mice can serve as model for complex partial&nbsp; with secondary generalization. Phenytoin and phenobarbitone are effective in this model.<\/p>\n\n\n\n<ul><li>quaking mice.<\/li><\/ul>\n\n\n\n<p>These are C57BL\/ 6 mutants with myelin defects, tremors, spontaneous or stimulus induced myoclonic and generalized tonic-clonic seizures. Handling induces Seizures in quaking mice. These seizures are blocked by phenytoin, phenobarb, carbamazepine and valproic acid. Quaking mice are useful for assessment of potential anticonvulsant drugs effective against focal motor seizures in humans.<\/p>\n\n\n\n<ul><li>Totterer Mice:<\/li><\/ul>\n\n\n\n<p>prone to spontaneous epileptic seizures, These mice are recognized by a broad-based ataxic gait. By 3 to 4 weeks of age they develop frequent partial and absence seizures. Spontaneous focal motor seizures occur few times a day, manifested as unilateral clonic jerks of limbs with secondary generalization. Ninety-three percent of the seizures last for 15 minutes or longer. These seizures can be suppressed by diazepam.<\/p>\n\n\n\n<p>Totterer mice also exhibit spontaneous petit mal seizures with synchronous 6-7\/sec spike-wave discharges in EEG. These spike-wave discharges last 0.3 to 10 sec and occur hundreds of times per day and are accompanied by a behavioral petit seizure<\/p>\n\n\n\n<p>These seizures are blocked by ethosuximide, diazepam and phenobarbital while phenytoin is not effective.<\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"262\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-49.png?w=480\" alt=\"\" class=\"wp-image-384\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-49.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-49-300x164.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<ul><li>Kindled rat seizure model: Administration of sub-convulsive electrical stimuli increases the intensity of the convulsions induced by these stimuli finally culminating in a full blow generalized seizure.<\/li><\/ul>\n\n\n\n<p>Kindling is progressive and permanent<\/p>\n\n\n\n<ul><li>Female SD rats are taken: Electrode is inserted in the right amydala and subconvulsive stimuli are given.<\/li><li>Endpoints- Seizure latency i.e. time from stimulation to the&nbsp; first sign of seizure activity, Seizure&nbsp; severity, Seizure&nbsp; duration<\/li><li>Deletion of gene in mice encoding receptor tyrosine kinase (TrkB) prevents epileptogenesis in kindling model.<\/li><\/ul>\n\n\n\n<ul><li>Clinical evaluation<\/li><li>Phase 1<\/li><li>Objectives: Study the single dose and multiple dose pharmacokinetics. Safety by determining the maximum tolerated dose.<\/li><li>Popu: healthy adult volunteers<\/li><li>Single dose<\/li><li>Parameters: t1\/2, PK characteristics, pp binding.<\/li><li>Any relationship between s\/e and max blood conc should be assessed.<\/li><li>Multiple dose<\/li><li>Dosing interval is determined by t1\/2 obtained from single dose studies<\/li><li>Parameters: Lab invest, PK. Neuropsychological parameters<\/li><li>Phase 2<\/li><li>Begin with open label exploratory studies: For assessing the titration rate, MTD, PK and drug interactions (Failure to discover interaction might l\/t substantial under or over dosing)<\/li><li>Multicenter, double-blind, placebo-controlled randomized, adjunctive therapy, parallel group design.<\/li><li>Object: short term efficacy and tolerability during add on therapy<\/li><li>Primary endpoint: % change in seizure frequency during maintenance phase a\/c\/t baseline. Responder rate (% of patients with 50% decrease in seizure frequency in maintenance phase a\/c\/t baseline). Secondary endpoints: worsening, adverse effects, % of seizure free, compliance<\/li><li>Popu: Adults with refractory epilepsy receiving 1-3 AEDs<\/li><\/ul>\n\n\n\n<p><strong>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Specific inclusion criteria<\/strong><\/p>\n\n\n\n<ul><li>a. Adults (ages 16 to 65) with seizures, defined according to the ILAE classification.<\/li><li>b. Patients should have non-controlled seizures despite a stable regimen with 1-3 established appropriate AEDs (The vagal nerve stimulator is considered as a drug).<\/li><\/ul>\n\n\n\n<ul><li>c. A defined minimum no. of seizures in the baseline phase (e.g. &gt; 6 observable seizures in 8 weeks and at least one seizure in any 4-week period during the baseline).<\/li><\/ul>\n\n\n\n<p><strong>Specific exclusion criteria<\/strong><\/p>\n\n\n\n<ol type=\"a\"><li>H\/o status epilepticus in the past year.<ol><li>Non-epileptic attacks (syncopes, pseudoseizures).<\/li><\/ol><ol><li>Significant&nbsp; psychiatric disorder.<\/li><\/ol><ol><li>Progressive CNS disorders (vascular malformations, high grade tumors, etc.).<\/li><\/ol><ol><li>Drug or alcohol abuse.<\/li><\/ol><ol><li>Previous poor compliance with therapy.<\/li><\/ol><ol><li>Pregnant or breastfeeding women.<\/li><\/ol><ol><li>Need for rescue benzodiazepines more frequently than once in the baseline period.<\/li><\/ol><ol><li>Seizure clustering.<\/li><\/ol><\/li><\/ol>\n\n\n\n<ul><li>Design: 4 parts.<\/li><li>Retrospective screening phase: to determine refractory status<\/li><li>Prospective baseline phase: Optimization of current AED. Stabilization of the disease.<\/li><li>Titration: Test drug dose increased upto MTD. Baseline AEDs might require adjustment d\/t interactions<\/li><li>Maintenance: should be of atleast 12 weeks to determine prolonged effect.&nbsp; Try to keep test and baseline AED dose stable.<\/li><\/ul>\n\n\n\n<ul><li>Phase 3.<\/li><li>Monotherapy<\/li><li>Short term refractory:<\/li><li>Outpatient conversion to monotherapy in refractory epilepsy<\/li><li>Object: E and S to test drug as monotherapy in patients with uncontrolled seizures<\/li><li>Endpoint: Time to exit based on exit criteria: Nth no of seizure, doubling of average monthly seizure rate, doubling of highest 2 day consecutive seizure rate, Emergence of new seizures<\/li><li>Design: Same as Phase 2<\/li><li>Inpatient: Presurgical conversion to monotherapy in refractory epilepsy. Efficacy&nbsp; is assessed in pre-surgical designs trials has limited relevance for long-term clinical use. Therefore, performance of this trial alone would not lead to FDA indication for use of a drug as monotherapy. It is now more often performed as a <strong>proof of principle study.<\/strong><\/li><li>Long term monotherapy:<\/li><li>Superiority in newly diagnosed patients<\/li><li>Object: E and T of new drug to standard as monotherapy<\/li><li>Endpoint: <strong>Time to first or second seizure<\/strong><\/li><li>Design: Same as phase 2<\/li><li>Non-inferiority: Patients with new onset epilepsy or previously diagnosed but currently untreated epilepsy.<\/li><li>Object: E and T for test drug to standard<\/li><li>Primary endpoint: <strong>proportion of seizure free patients at 6 months<\/strong><\/li><\/ul>\n\n\n\n<ul><li>Adjuctive therapy: Similar to phase 2.<\/li><\/ul>\n\n\n\n<ul><li>Phase 4: Prospective cohort study design. Detect unusual s\/e. Long term adr. Alteration of therapeutic effct over long term. Teratogenic effects. Drug interactions<\/li><\/ul>\n\n\n\n<ul><li>Trials in children<\/li><li>Essential to evaluate effect of drug on growth and development and cognitive function.<\/li><li>Don\u2019t include children in Phase 2 and 3 unless disease is specifically for children<\/li><li>Safety has to be done first in adults<\/li><li>Results of efficacy trials in adults can be extrapolated in children &gt;4 years<\/li><li>&lt;4 years: short term assessment of response by video monitoring is sufficient if efficacy is proven in older children<\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Evaluation of anti-epileptic drugs: Seizure: Paroxysmal event due to abnormal, excessive, hyper synchronous discharges from an aggregate of central nervous system (CNS) neurons. Epilepsy: Recurrent seizures due to chronic, underlying process, defined as two or more unprovoked seizures. Indian prevalence: 3.0-11.9 per 1,000 population Mechanism of seizure initiation 1. Initiation Phase &nbsp;High-frequency bursts of action[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/379"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=379"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/379\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=379"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=379"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=379"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}