بسم الله الرحمن الرحيم

Pharmacoresistant Epilepsy: How..!?

How to define? How to predict?How to manage?

ByTamer Belal. MD (PhD)Lecturer of NeurologyMansoura University

Simon Shorvon 2005 stated that “ epilepsy is regarded as sufficently intractable to contemplate surgery if it has been continuously active for 5 years (or less in severe epilepsy) in spite of adequate trials of therapy with three or more main-line antiepileptic drugs, and if seizures are frequent (More than one per month) ”

Juan Carlos 2007 defined RE as the persistence of correctly diagnosed unprovoked epileptic seizures that recur so frequently that they interfere with patients’ daily lives and cause personal dissatisfaction despite appropriate antiepileptic drug treatment (Relevant to type of seizure or epileptic syndrome ,maximum tolerated dose and good compliance)

Definitions

Definitions

Wolfgang Löscher 2009 define drug resistance as the persistence of seizures despite treatment with a range of AEDs used alone or in combination at maximum tolerated doses

Failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom.

With this definition, "drug resistant" replaces "intractable" or "refractory.”

Seizure free is either be

Seizure free for at least 1 year OR

3 times the longest preintervention inter-seizure interval (whichever is longer) “Rule of 3"

ILAE Commission on Therapeutic Strategies Task Force (Kwan et al. 2010

Definitions

• Earlier studies suggested that many patients respond to monotherapy but fewer and fewer patients respond to combination therapy.

Monotherapy

70% controlled*

30% poorly managed

30% controlled* on 2 drugs

Combinations of two or more drugs provide little

more benefit

Mattson, 1992

* Controlled was defined as adequately managed but not necessarily seizure-free

AED Response – Established AEDs

• 525 untreated patients (470 drug-naïve)

1st Monotherapy

2nd Monotherapy

60% controlled*

40% difficult to

control

3rd Monotherapy

1% controlled*

99% not controlled

• Only 3% were controlled with two AEDs, and none with three.

Brodie & Kwan, 2002

*Controlled was defined as seizure-free

AED ResponseNewer is Not Always Better

Problem of Drug refractory epilepsy

In the UK alone, where 80000 people have refractory epilepsy, the cost of epilepsy overall is at least £2000 million/year

A US study in the early 1990s estimated that the annual cost of refractory epilepsy in adults exceeds $11,745 per person

Costs were correlate with severity of illness and that patients who have intractable seizures incur a cost eight times greater than in those whose epilepsy is controlled

People with pharmacoresistant epilepsy are about two to 10 times more likely to die compared with the general population and The risk is inversely linked to seizure control.

The costs of resistant epilepsy:

Approximately 20-40% of patients with primary generalized epilepsy and up to 60% of patients who have focal epilepsy develop drug resistance during the course of their condition, which for many is lifelong

When seizures have failed to respond to two or three appropriate antiepileptic drugs, the chance of significant benefit from other drugs is 10% or less.

Those who get no response or only a partial response to drugs continue to have incapacitating seizures that lead to significant

Neuropsychiatric and social impairment, Lower quality of life, Greater morbidity, and A higher risk of death.

Problem of Drug refractory epilepsy

Clinical predictors that have been associated with PRE

Early onset of seizures(before age of one year)

High seizure density (number of seizures per time) before treatment initiation

Having more than one type of seizure (Syndrome)

Long history of poor seizure control (failure of first drug)

Multiple seizures after treatment initiation

Family history of epilepsy

Remote symptomatic etiology (patients with a history of brain infection or head trauma)

Certain structural abnormalities (cortical dysplasia, hippocampal sclerosis)

Certain EEG abnormalities, such as persistent focal slowing, or high frequency of focal epileptiform abnormalities

Cognitive disability (Mental retardation)

History of status epilepticus.

Abnormal neurological examination

Psychiatric comorbidity

Kwan P, Brodie MJ. CNS Spectr. 2004;9:110-119.

Misdiagnosis of epilepsyExample: patients with psychogenic non epileptic seizures (misdiagnosed and inappropriately treated with multiple antiepileptic drugs) and misdiagnosis of another condition (syncopal, cardiac, neurological, metabolic )

Misdiagnosis of epilepsy type, leading to inappropriate drug selectionExample: misdiagnosis of temporal lobe seizures for absence seizures, or vice versa

Inappropriate assessment of response or lack of responseExamples: drug interactions leading to increased side effects and decreased tolerability

Inappropriate patient behavior & Inadequate drug levelsExamples: poor compliance, detrimental lifestyle

Causes of apparent or “false” pharmacoresistant epilepsy

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Any proposed mechanism must fulfill a series of requirements to be considered valid.

It must be Detectable

in epileptogenic brain tissue

It must have functional capacity

from the pathophysiological

point of view

It must be shown that it is an active

mechanism in human epilepsy

Modification of this mechanism

should affect the phenomenon of

resistance to AEDs

Disease-related mechanismsAetiology of disease (epilepsy syndromes)Progression of diseaseStructural brain alterations and/or network

changes Alterations in drug target(s)Alterations in drug uptake into the brain

Drug-related mechanisms Ineffective mechanism of drug actionLow safety margin of AED precludes sufficiently

high brain levelsLoss of efficacy (tolerance) during chronic

treatment

Pharmacogenetic mechanisms (patient characteristics)

Gene polymorphisms that affect pharmacokinetics or pharmacodynamics of AEDs

Possible mechanisms of drug resistance

Biologic basis of pharmacoresistant epilepsy

Alterations of drug target(s)

Structural brain alteration and / or network changes

Progression of disease (Seizures Clusters)

Etiology (Epilepsy Syndrome)

Disease-related mechanisms

Alterations of drug uptake

Low safety margin of AED precludes sufficiently high brain level

lack of antiepileptogenic (disease-modifying) actions (ineffective mechanism )

Development of tolerance

Drug-related mechanisms

Biologic basis of pharmacoresistant epilepsy

Metabolites. & environmental factors play a role in the development or expression of pharmacoresistance

Proteins

RNA Age-related changes in pharmacokinetic and pharmacodynamic (age-dependent pharmacoresistance

DNA variations (genotype) pharmacogenetics.

Pharmacogenetic mechanisms

Biologic basis of pharmacoresistant epilepsy

Etiology (Epilepsy Syndrome)

Disease-related mechanisms

Epileptic encephalopathiesSymptomatic partial epilepsiesTemporal lobe epilepsy

Biologic basis of pharmacoresistant epilepsy

Disease-related mechanisms

Progression of disease (Seizures Clusters)

Epilepsy may switch in a significant proportion of patients in the course of the disorder from being drug resistant to becoming controlled and vice versaSeizure clusters, defined as three or more seizures per 24 h, occurring often as many as 15 years after starting treatment, increased the risk of resistant epilepsy by 3 compared with those without clusters

Biologic basis of pharmacoresistant epilepsy

Disease-related mechanisms

The network hypothesis of drug resistance after surgery is based on the existence of nonresected limbic or extralimbic seizure generators left behind . ‘rewiring the brain’

Structural brain alteration and / or network changes

Dentate gyrus functions as Gatekeeper preventing the propagation of synchronized activity from the entorhinal cortex into the seizure-prone hippocampus

Biologic basis of pharmacoresistant epilepsy

Disease-related mechanisms

Alterations of drug target(s)Target Hypothesis

Acquired alterations to the structure and/or functionality of target ion channels and neurotransmitter receptorsSubunit composition of these channels is altered, resulting in channels with lower AED sensitivityReceptor trafficking (internalisation)

Shift from adult inhibitory to neonatal excitatory GABAA receptors

Biologic basis of pharmacoresistant epilepsy

Disease-related mechanisms

Alterations of drug uptakeTransporter hypothesis

Over expression of (multi)drug efflux transporters in brain and other tissues.

Biologic basis of pharmacoresistant epilepsy

Drug-related mechanisms

Development of tolerance

Pharmacokinetic (metabolic)

Pharmacodynamic (functional)

induction of AED-metabolizing enzymes (first-generation AEDs)

Increasing the expression of P-gp (newer AEDs)

adaptation’of AED targets (loss of receptor sensitivity)

Biologic basis of pharmacoresistant epilepsy

In some patients, resistance is present from the time of onset of the very first seizure, before antiepileptic drug is even started.

Patients with newly diagnosed epilepsy for whom the first drug was ineffective had only an 11% probability of future success, compared with 41% to 55% in patients who had had to stop taking the drug because of intolerable side effects or idiosyncratic reactions.

In some patients, epilepsy is initially controlled but then gradually becomes refractory. This pattern may be seen, in childhood epilepsies or in patients with hippocampal sclerosis

In some patients, epilepsy has a waxing-and waning pattern: ie, it alternates between a remitting (pharmacoresponsive) and relapsing (pharmacoresistant) course.

Changes in drug bioavailability, local concentration of the drug in the brain, receptor changes, the development of tolerance, and interactions with new medications may be implicated, though the exact mechanism is not understood

3

Waxing and waning

resistance

2

Progressive drug

resistance

1

De novo drug resistance

Patterns of drug resistance

Pharmacokinetic or “transporter”

hypothesis

Increased action of membrane transporter proteins involved in cellular defense that expel endogenous toxins and xenobiotics (understood like biologic substances out of its habitual place) to the outside of the cell, thus preventing adequate concentrations of AEDs from being reached in the brain despite adequate serum concentrations, because these drugs do not penetrate the blood-brain barrier well

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Structural or functional modifications in different “targets” where AEDs act, either ion channels, neurotransmitter receptors or enzyme systems related to the release, reuptake, and metabolism of neurotransmitters

Pharmacodynamic or “target” hypothesis

Alteration of the mechanisms of L-DOPA uptake in basal gangliaAlteration of the mechanisms regulating chloride and potassium homeostasisSpecific alterations in certain genes involved in susceptibility to seizures.

Other Hypotheses

Pharmacokinetic or transporter hypothesis of drug resistance. Increased expression of membrane transporter proteins prevents adequate penetration of AEDs into the brain parenchyma

Antiepileptic Drugs

Endothelial cellBlood-brain

Barrier

Blood

Brain

Concentration of AED in Tissue

OtherP-GPMRP

Membrane transporter proteins are involved in numerous vital processes:

- Expulsion of toxic molecules- The transport of nutrients- The transport of peptides and hormones- The transport of drugs

These proteins are encoded by genes belonging to the ATP-binding cassette (ABC) transporter superfamily, of which 7 subfamilies present in humans are known

Various genes belonging to the ABCB, ABCC, and ABCG subfamilies are involved in MDR.

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Pharmacokinetic or “transporter” hypothesis

Three major groups of ABC transporters are involved in multidrug resistance

1. P-glycoprotein (P-gp/MDR1)

2. The multidrug resistance associated proteins (MRP1, MRP2, and probably MRP3, MRP4 and MRP5),

3. ABCG2 protein, an ABC half-transporter also called BCRP or Breast Cancer Related Protein.

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Pharmacokinetic or “transporter” hypothesis

THE BIOCHEMICAL BARRIER

The most important efflux transporters which so far identified at the blood–brain barrier belong to the class of ATPbinding-cassette (ABC) transporters Oatp=Organic anion transporting polypeptide 3 Pharmacol Rev 60:196–209, 2008

Blood Brain BarrierBrain Capillary Endothelium

Tig

ht

Ju

nc

tio

n

Tig

ht

Ju

nc

tio

n

abluminal

Luminal

ATP ATP ATP ADPADPADP

P-glycoprotein BCRP Mrp 1, 2, 4 Oatp2

Oatp3Oatp2

BLOOD

BRAIN

abluminal

Luminal

P-glycoprotein may transport cytotoxic drugs directly from the cell membrane, before such drugs enter the cytoplasm (1), or from the cytoplasm (2), limiting the concentration of such drugs at the target (DNA or tubulin). Highly lipophilic drugs enter the cell by passive diffusion (3). Inhibitors of P-glycoprotein–mediated transport may be carried through the blood supply (e.g., steroid hormones and agents that reverse the multidrug-resistance [MDR] phenotype) (4), or hypothetical natural substrates may be produced in the cell (5).

The fact that some of these proteins are also found in glial cells and neurons has led to the emergence of a new concept, that of the “second barrier,” mediated by the protein transporters of the cellular components of the brain parenchyma, which would act in concert with the blood-brain barrier to restrict the access of certain drugs to the CNS

Overexpression of transporter proteins is regionally selective, affecting the epileptogenic areas of the brain but not other unaffected areas

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Pharmacokinetic or “transporter” hypothesis

A novel membrane transporter not belonging to the ABC transporter family has recently been described, RLIP76 (RALBP1), which may have a predominant role in resistance to AEDs.

It has been shown that it is expressed exclusively in brain endothelial cells, and is especially prominent in epileptic tissue of patients operated on for RE.

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Pharmacokinetic or “transporter” hypothesis

Mechanisms of Overexpression of Membrane Transporter Proteins

It is still not known whether increased expression of these drug transporters is acquired or constitutional.

The reason why seizures may cause this increase in transporter proteins is also not known, but it could be explained by the “second barrier” hypothesis, which would serve to protect the brain during transient opening of the blood-brain barrier, which typically occurs in response to prolonged seizure activity.

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Pharmacokinetic or “transporter” hypothesis

Modification of the functional consequence of membrane transporter proteins that results in decreased distribution of AEDs in the brain is a promising therapeutic strategy for the treatment of RE,

Tariquidar (elacridar), a selective inhibitor of P-gp without antiepileptic activity, in combination with phenytoin, almost completely controlled seizures (although temporarily) in a rat model of temporal lobe epilepsy,

Improvement in seizure control after the administration of verapamil (a nonselective P-gp inhibitor),but, apart from their anecdotal character, it should be kept in mind that verapamil also blocks calcium channels and inhibits the metabolism of various AEDs, and so it cannot be assumed that the improvement was due to the inhibitory effect on P-gp.

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Pharmacokinetic or “transporter” hypothesis

P-Glycoprotein Activity is physiologically down regulated by:• Nitric Oxide• Endothelin 1• VEGF

P-Glycoprotein Activity/Expression is Up regulated by:• Dexamethasone• Cyclooxygenase activity/Prostaglandin E2• Pregnane X Receptor (Senses xenobiotic such as

glucocorticoids, anticancer drugs, or antiepileptic drugs)• Glutamate/NMDA receptor signaling• Wnt/β-catenin signaling

Pharmacology & Therapeutics 125 (2010) 118–127

Pharmacokinetic or “transporter” hypothesis

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

The key element of this hypothesis is the existence of an intrinsic or acquired structural or functional change in the molecular target of the AED.

Broadly speaking, these therapeutic targets can be divided into 2 large groups of molecules:

o Subunits of voltage-gated ion channels (Na, Ca, and K channels)o Receptors of neurotransmitters related to neuronal excitation (GABA

and glutamic acid).

The alteration in the target that interferes with the mechanism of action of the AED and leads to RE may be

Intrinsic genetically determined OR Acquired (develop over time as the consequence of

exogenous factors ).

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Pharmacodynamic or “target” hypothesis

Dopaminergic neurotransmission in the basal ganglia to RE and its role as a modulator of cortical excitability, which may alter interindividual response to AEDs

Alterations in the mechanisms regulating chloride and potassium levels in epileptogenic tissue may have a similar role.

Genetic alterations (supported by some experimental studies). A correlation has been established between a type of SNP in the IL-1 gene and

the development of hippocampal sclerosis, suggesting that it could be a prototypical genetic mediator of intrinsic resistance to AEDs

Gene encoding dopamine β-hydroxylase, suggested in initial studies

SNPs in the cellular prion protein gene with the development of acquired resistance to AEDs in temporal lobe epilepsy initially found a strong association with particular type of polymorphism

MECHANISMS OF PHARMACORESISTANCEMECHANISMS OF PHARMACORESISTANCE

Other hypotheses

Initiating evente.g.,genetic malformations,head

trauma,febrile seizures,infections, stroke, status epilepticus

Onset of epileptogenesise.g.,by “second hit”, polymorphism,

susceptibility genes, critical modulators, comorbidities

Functional and structural alterations during epileptogensis

e.g.,hyperexcitability of neurons and/or neuronal circuits, alterations in expression and function of receptors and ion channels( in part recapitulating ontogenesis), neurnal loss,

neurogenesis, axonal and dendritic sprouting, gliosis, inflammation

Cognitive and behavioral alteration

Progression of epilepsy

Spontaneous seizures(clinical onset of

epilepsy)

Chronic epilepsy often pharmacoresistant

Repair (or control)

Failure to Repair

No consequence

No Progression

Therapeutic intervention

Antiepileptogenic/neuroprotective

Anticonvulsant

Disease-modifyingSteps in the development and progression of temporal lobe epilepsy and possible therapeutic interventions. The term epileptogenesis includes processes that take place before the first spontaneous seizure occurs to render the epileptic brain susceptible to spontaneous recurrent seizures and processes that intensify seizures and make them more refractory to therapy (progression). The concept illustrated in the figure is based on both experimental and clinical data.

Uncontrolled epilepsy?Lack of seizure-free period for 12 consecutive months in spite of two or three suitable two or tree suitable antiepileptic drug trials?

Is the diagnosis of epilepsy

correct?

Refer to a tertiary epilepsy center

Considerpharmacoresista

ntepilepsy

Rule out apparentor “false”

pharmacoresistance

Generalized epilepsy

Focal epilepsy

Unclassifiable epilepsy

Video-elctroencephalogra

phy

Epilepsy diagnosisconfirmed

Nonepileptic events

(psychogenic or other)

Appropriate referral depending on etiology

Clinical approach to patients with pharmacoresistant epilepsy

Phase A

Generalized epilepsyFocal epilepsy

Unclassifiable epilepsy

OR

Magnetic resonance imaging (MRI) epilepsy protocol Interictal PET, Ictal SPECTMagnetoencephalographyNeuropsychological assessment Functional MRI and intracarotid amobarbitalprocedure as needed

Potential surgicalcandidate

Review in patientManagement conference

Unfavorable surgical

candidate

Nonlesional focal epilepsyor

Discordant neurophysiology and imaging data

orEloquent cortex at risk

MRI lesion concordant with

electroencephalography (EEG) and other noninvasive studies

Curative epilepsy surgeryLobectomy LesionectomyTailored cortical esectionMultilobar resection

Invasive EEG for possible

localization and resection

Localized ictal onset not overlapping with eloquent

cortex

Poorly localizable ormultifocal ictal

onset;or onset in eloquent

cortex

Vagus nerve stimulation with or without corpus

callosotomyExperimental therapies

Ketogenic diet in children Steroid and new AED

Specialized diagnostic and treatment options for patients with

pharmacoresistant epilepsy

Phase B

Phase C

Failure of past drug developments is likely because of a neurocentric approach neglecting the role of the blood–brain barrier, inflammation, astrocytes, mitochondria and genetic disposition in the disease.

There has been relatively little improvement in AED efficacy since the introduction of phenobarbital in 1912, so that still more than 30% of epilepsy patients are resistant to AEDs with up to 90% with certain types of focal epilepsies.

Future targeted therapies could be coupled to seizure-forecasting systems to create “smart” implantable devices that predict, detect, and preemptively treat the seizures in a “closed-loop” fashion

Novel Epilepsy Therapies

Direct stimulation targets presumed epileptogenic brain tissue such as the neocortex or hippocampus

Indirect stimulation targets presumed seizure-gating networks such as in the cerebellum and various deep brain nuclei in the basal ganglia or thalamus (deep brain stimulation), which are believed to play a central role in modulating the synchronization and propagation of seizure activity.

Targeted electrical stimulation

Novel Epilepsy Therapies

Direct delivery of drugs into the epileptogenic brain tissue holds promise, particularly for patients whose foci cannot be surgically removed.

Convection-enhanced delivery (CED) provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches.

CED infusions of non diffusible peptides that inhibit the release of excitatory neurotransmitters, including ω-conotoxins and botulinum neurotoxins, produce long-lasting (weeks to months) seizure protection in the rat amygdala-kindling model

To date no clinical study has explored the utility of intraparenchymal or intraventricular antiepileptic drug delivery in humans

Novel Epilepsy Therapies

Local drug delivery

In ex vivo gene therapy, bioengineered cells capable of delivering anticonvulsant compounds might be transplanted into specific areas of the brain.

In vivo gene therapy would involve delivering genes by viral vectors to induce the localized production of antiepileptic compounds in situ.

In epilepsy, particularly in TLE, cell transplantation could potentially be of value in four different ways :

By repairing the damage in the hippocampus, By counteracting or modifying the development of epilepsy, By suppressing seizures in AED-resistant patients with

established epilepsy or By counteracting the progression of epilepsy.

Novel Epilepsy Therapies

Cell and gene therapies

Used in patients with focal epilepsy when the seizure focus is located in eloquent or surgically challenging brain regions that are associated with an unacceptably high incidence of complications after open surgery

- lesional epilepsy associated with arteriovenous malformations, cavernomas, and tumours

- Mesial temporal sclerosis and hypothalamic hamartomas

The antiseizure effect is commonly delayed and unpredictable late complications

Novel Epilepsy Therapies

Radiosurgery

Results of transplantation of fetal neurons in rat models of temporal lobe epilepsy

Potential candidates, and their known functions, associated with pharmacogenetics of antiepileptic

drugs

Enzymes involved in the metabolism of commonly prescribed antiepileptic drugs

Genetic causes of refractory epilepsies

Genotype–phenotype correlations. DRPLA, dentate-rubro-pallido-Luysian atrophy; GEFSþ, epilepsy with febrile seizures plus; IGE, idiopathic generalized epilepsy; LD, Lafora body disease; MAE, myoclonic astatic epilepsy; MERFF, yoclonic epilepsy with ragged red fibres; NCL, neuronal ceroid lipofuscinosis; TLE, temporal lobe epilepsy; ULD, Unverricht–Lundborg disease.

Greater efficacy than other drugs in the treatment of refractory epilepsies

The ability to prevent or delay the onset of epilepsy (epileptogenesis), or at least modify its progression;

Broad usefulness in non-epileptic CNS disorders

Fewer adverse effects than available drugs

Ease of use, such as rapid titration, linear pharmacokinetics, lack of drug interactions, or a longer half-life that enables once or twice daily doses or extended protection if a dose is missed.

A new AED is successful if it has at least one of thefollowing properties:

More than 20 compounds are at various stages of clinical development

These include

drugs with chemical structures that do not resemble existing AEDs.

derivatives of existing drugs that are developed as follow-up compounds with potentially improved properties

A new AED is successful if it has at least one of thefollowing properties:

Potential antiepileptic compounds in various stages of clinical development

Principal mechanisms of action of the newer antiepileptic drugs include voltage-dependent ion channel blockade, enhancement of inhibitory neurotransmission, and reduction of excitatory neurotransmission.LaRoche, S. M. et al. JAMA 2004;291:605-614

Proposed mechanisms of action of currently available AEDs at excitatory and inhibitory synapses.

Drug Brand US UK France

acetazolamide Diamox 27 July 1953 1988

carbamazepine

Tegretol 15 July 1974 1965 1963

clobazam Frisium 1979

clonazepam Klonopin/Rivotril

4 June 1975 1974

diazepam Valium 15 November 1963

divalproex sodium Depakote 10 March 1983

ethosuximide Zarontin 2 November 1960

1955 1962

ethotoin Peganone 22 April 1957

felbamate Felbatol 29 July 1993

fosphenytoin Cerebyx 5 August 1996

gabapentin Neurontin 30 December 1993

May 1993 October 1994

lamotrigine Lamictal 27 December 1994

October 1991

May 1995

lacosamide Vimpat

Anticonvulsant drugs together with the date their marketing was approved in the US, UK and France

Drug Brand US UK France

levetiracetam Keppra 30 November 1999

29 September 2000

29 September 2000

mephenytoin Mesantoin 23 October 1946

metharbital Gemonil 1952

methsuximide Celontin 8 February 1957

methazolamide

Neptazane 26 January 1959

oxcarbazepine Trileptal 14 January 2000

2000

phenobarbital 1912 1920

phenytoin Dilantin/Epanutin

1938 1941

phensuximide Milontin 1953

Anticonvulsant drugs together with the date their marketing was approved in the US, UK and France

Drug Brand US UK France

pregabalin Lyrica 30 December 2004

6 July 2004 6 July 2004

primidone Mysoline 8 March 1954

1952 1953

sodium valproate

Epilim December 1977

June 1967

stiripentol Diacomit 5 December 2001

5 December 2001

pregabalin Lyrica 30 December 2004

6 July 2004 6 July 2004

primidone Mysoline 8 March 1954

1952 1953

Anticonvulsant drugs together with the date their marketing was approved in the US, UK and France

Drug Brand US UK France

tiagabine Gabitril 30 September 1997

1998 November 1997

topiramate Topamax 24 December 1996

1995

trimethadione Tridione 25 January 1946

valproic acid Depakene/Convulex

28 February 1978

1993

vigabatrin Sabril 21 August 2009

1989

zonisamide Zonegran 27 March 2000

10 March 2005

10 March 2005

Anticonvulsant drugs together with the date their marketing was approved in the US, UK and France

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