Page 1 of 28
`
`JAZZ EXHIBIT 2015
`Ranbaxy Inc. (Petitioner) v. Jazz Pharms. Ireland Ltd. (Patent Owner)
`Case IPR2016-00024
`
`

`
`lnlernulioncil Editorial Board
`
`I-\.C. Altomuro, Milan, Italy
`M. Ansseou, Large, Belgium
`i2..J. Eloldessdrlnl, Belmont, MA, USA
`P. Bach. Hillemrl, Demrtrtrlr
`M. Bicilet. Jerusalem, Israel
`J. Blller. Indianapolis, IN, USA
`H. Biodc1ty,Randzui'ck, NSW, Australia
`M.J. Brodie. Glasgow, Scofliiiid
`GD. Burrows, Heidelberg, VIC, Australia
`M.C. Chamberlain. Los Angeles, CA, USA
`D.S. Charnev, Betliescla, MD, USA
`J.A. den Boer. Grortirtgeri, The Nctlierlnnds
`GA. DOfll'IC|l‘l, Heidelberg, VIC, Australia
`M.J. Eadie. Brisbane, QLD, Auslmlia
`H.M. Ernrlch. Hanover, Germrmy
`MR. Forlow, Indianapolis, IN, USA
`GA. FCIVCI. Bologna, Italy
`w.w_ Flelschhocker, ltinslmick, Austria
`D.J. Greanblott. Boston, MA, USA
`C". Guillemlnciult. Stanford, CA, USA
`I. Hlndmcirch. Godalming, Englrmd
`M.W. Jann, Atlanta, GA, USA
`F.J. Jlménerdiménez, Mndrirl, Sprain
`H. Katya. Tokyo, lapmi
`re. Kerwin. London, England
`S.P. Kutcher. Halifax, NS, Cnmzda
`M. Lacter. London, England
`J.F. Lcirsen. Starirmgcr, Norway
`B. Leonard, Galwni , Ireland
`E. Peruccci. Pavia, Italy
`RM. Post. Betliesrltr, MD, USA
`AM. Ropoport, Slmnford, CT, USA
`D.A. Revlcki, Bethesda, MD, USA
`K.L. Roos. lndianapolis, IN, USA
`J.F. Rosenboum. Boston, MA, USA
`J.W. Sander. Clralfont St. Peter, Englamt
`S.C. Schcichler, Boston, MA, USA
`S.A. Schug. Perth, WA, Aitstrnlia
`l.ShoL.I|son.Racl1esler, NY, USA
`S.D. Silberstein. Plii'ladclpl1r'ri, PA, USA
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`Page 2 of 28
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`Page 2 of 28
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`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`REVIEW ARTICLE .%”§l’o;”il‘a§?§§r3.‘3£L3ls%‘;°.5‘533
`to Adi: lnternairormi Limited. All rights reserved
`
`Basic Pharmacology of Valproate
`A Review After 35 Years of Clinical Use for the
`
`Treatment of Epilepsy
`
`Wolfgrmg Liisclzer
`
`Department of Pharmacology, School of Veterinary Medicine, Toxicology and Pharmacy,
`Hannover, Germany
`
`Contents
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`1. Historical Background .
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`2. Overview of Clinical Use .
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`3. Epilepsy and Epileptic Seizures .
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`4. Animal Models of Epilepsy
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`5. Effects in Experimental Models of Epilepsy and Epileptic Seizures .
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`5.1 Early versus Late Effects
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`5.2 Antiepileptogenic and Neuroprotective Effects .
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`5.3 Proconvulsont Effects
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`5.4 Other Pharmacodynarnic Effects
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`5.5 Pharmacokinetic and Pharrnocodyncimic issues
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`6:. Effects on Epiieptltorrn Discharges in in Vrfro and in Viva Preparations .
`7. Mechanisms of Action .
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`7.1 Effects on Excitaloility orinhibition
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`7.2 Effects on ion Channels .
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`7.2.1 Sodium Channels .
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`7.2.2 Potassium Channels
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`7.2.3 Calcium Channels .
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`7.3 Biochemical Effects
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`7.3.1 Effects on the waminobutyric Acid (GABA) System .
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`7.3.2 Effects on 7-Hydroxybutyrate. Glutamate and Aspartate .
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`7.3.3 Effects on Serotonin and Dopamine .
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`7.3.4 Other Biochemical Effects .
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`8. Possible Explanations for the Early and Late Effects .
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`9. Conclusions .
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`. 6:59
`. 670
`. 1570
`. on
`. 672
`. 672
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`(5741
`. 674
`. 6274
`. 675
`. 675
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`. {:79
`. 080
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`. oar
`. 681
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`(:86
`. 68?
`. 687
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`. 089
`
`AbSlTClC‘i
`
`Since its first marketing as an antlepiieptic drug (AE1)) 35 years ago in France,
`vaiproale has become established worldwide as one of the most widely used
`AEDs in the treatment of both generalised and partial seizures in adults and
`children. The broad spectrum of antiepilcptic efficacy of valproate is rellected in
`preclinical in i.=r'w; and in wtro models, including a variety of animal models of
`seizures or epilepsy.
`There is no single mechanism of action of valproate that can completely ac-
`count for the numerous effects of the drug on neuronal tissue and its broad clinical
`
`Page 3 of 28
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`Page 3 of 28
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`

`
`activity in epilepsy and other brain diseases. In view of the diverse molecular and
`cetlular events that underlie different seizure types, the combination of several
`neurochelnical and neurophysiological mechanisrns in a single drug molecule
`might explain the broad antiepileptic efficacy of valproate. Furthermore, by act-
`ing on diverse regional targets thought to be involved in the generation and prop-
`agation of seizures, valproate may antagonise epileptic activity at several steps
`of its organisation.
`There is now ample experimental evidence that valproate increases turnover
`of y—aminobutyric acid (GABA) and thereby potentiates GAB/kcrgic functions
`in some specific brain regions thought to be involved in the control of seizure
`generation and propagation. Furthermore, the effect of vnlproale on neuronal
`excitation mediated by the N—methyl—D—aspa.rtate {NMDA) subtype of glutamate
`receptors might be important for its anticonvulsant effects. Acting to alter the
`balance of inhibition and excitation through multiple mechanisrns is clearly an
`advantage for valproate and probably contributes to its broad spectrum of clinical
`effects.
`
`Although the GABAergic potentiation and glutainatei'NMDA inhibition could
`be a likely explanation for the anticonvulsant action on focal and generalised
`convulsive seizures, they do not explain the effect of valproate on nonconvulsive
`seizures, such as absences. In this respect, the reduction of y—hyd1-oxybutyrate
`(GHB) release reported for valproate could be of interest, because GHB has been
`suggested to play a critical role in the modulation of absence seizures.
`Although it is often proposed that blockade of voltage-dependent sodium Cur—
`rents is an important mechanism of antiepileptic action of valproate, the exact
`role played by this mechanism ofaction at therapeutically relevant concentrations
`in the mammalian brain is not clearly elucidated.
`By the experiniental observations summarised in this review. most clinical
`effects ofvalproate can be explained, although much remains to be learned at a
`number ofdifferent levels about the tnechanisms of action of valproate. In view
`oflhe advances in molecular neurobiology and neuroscience, future studies will
`undoubtedly further our understanding ofthe mechanisms of action ofvalproate.
`
`Valproic acid or valproate, a major and well es-
`tablished first—line antiepileptic (anticonvulsant)
`drug (AED}, is one of the most widely used AEDS
`in the treatment of different types of epilepsy.l‘~2l
`Valproate is the trivial name for 2—n—propylpentanoie
`acid (also called n-dipropylacetic acid). As a sim-
`ple branched—chain fatty acid, it differs markedly
`in structure from all other AEDs in clinical use.
`
`time, valproate was used as a vehicle to dissolve
`the active ingredient in testing the anticonvulsant
`activity of new compoundslsi The positive results.
`whatever the drug and the dose tested, led to the
`testing of valproate itself and to confirmation that
`it was effective against drug-induced seizures. The
`first clinical trials of the sodium salt of valproate
`were reported in 1964 by Carraz ct al,,lf‘l and it was
`first marketed in France in 1967.
`
`1. Historical Background
`
`Valproate was first synthesised in 1882 by Bur-
`ton,l3l but there was no known clinical use until its
`anticonvulsant activity was fortuitously discov~
`ered by Pierre Eymard in l962 in the laboratory of
`G. Carraz, as published by Meunier et al.l‘” At that
`
`2. Overview of Clinical Use
`
`Valpronte has been used for the treatment of
`epilepsy for nearly 35 years and is currently mare
`lceted in over [00 countries. Since its introduction
`
`into clinical use, valproate has become established
`
`E Aclls International Limited All rights resemad
`
`ens mugs 2on2; to no)
`
`Page 4 of 28
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`Page 4 of 28
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`

`
`671
`Basic Pharrnacoiogy of Valpr-oate
`
`worldwide as a major AED with a wide spectrum
`of activity against a broad range of seizure disor'-
`ders. Controlled clinical trials have demonstrated
`that it has similar eff'icacy to ethosuximide in the
`treatment of absence seizures and to carbamaze-
`
`pine, phenytoin and phenobarbital (phenobarbi-
`tonc) in the treatment ofboth tonic-clonic and par-
`tial seizures.l7'”l Furthermore. valproate compares
`favourably with newer AEDs, such
`vigabatrirrllzl
`and oxcarbazepine,ll3l in both efficacy and toler-
`2rbility.“‘“
`Results from numerous clinical trials suggest
`that valproate probably has the widest spectrum of
`antiepileptic activity of all established AEDs in
`both children and adults with epilepsy.”-”’l In ad-
`dition to partial and generalised seizures, valproatc
`has demonstrated efficacy in the t1'eatment of syn-
`dromes known to be very refractory, such as
`Lennox-Gastaut syrrdromei”-“*1 and West syn-
`drome.ll9l This gives valproate special signifi-
`cance fo1' the t1'eatrnent of patients with mixed sei-
`zure types who have highly refractory symptoms] Ml
`Furthermore. as a consequence of its b1'oad spec-
`trum of antiepileptic activity and as opposed to
`many other AEDS, there is no contraindication to
`the rise of valproate in any type of seizure or epi-
`lepsy.l"‘l
`Valproate is tolerated well in most patients,l2"l
`Most adverse effects are mild to moderate in inten-
`
`sity, and hypersensitivity reactions are rare. A
`comparison with other widely used AEDS showed
`that valproate causes fewer neurological adverse
`effects and fewer skin rashes than phenytoin, phe-
`nobarbital and primidone, and its tolerability and
`safety appear to be similar to that of carbamaze-
`pine.l3"l Main areas of concern with valproate are
`teratogenlcity and idiosyncratic liver toxicity.
`With respect to teratogenicity, recommendations
`on the use of valproate in women who plan to con-
`ceive, such as monotherapy with the lowest effec-
`tive close, have lowered this risk, so that with these
`recommendations val proate does not appear to in-
`duce birth defects with any greater frequency than
`other AEDs.l3“l With respect to idiosyncratic liver
`toxicity, identification ofhigh-risk patients such as
`
`children under 2 year's with severe epilepsy and
`mental retardation receiving polytherapy has con-
`siderably reduced its incidenceflml
`The present review summarises the major phar-
`macological effects of valproate that appear to be
`of importance for its unique antiepileptic efficacy.
`For a more comprehensive survey of the multiple
`effects of valproate, including its adverse effects
`attd pharrnacokinetics. several previous reviews
`and monographs are available.l‘i3-153'-231 Further-
`more, the major aspects of the clinical use of val-
`proate. its advantages and limitations and their cor-
`relation with pharrnacological findings are covered
`in the review by Peruccamlthat also appears in this
`issue of CNS Drugs.
`
`3. Epilepsy and Epileptic Seizures
`
`Epitepsy, a common neurological disorder char-
`acterised by recurrent spontaneous seizures, is a
`major, worldwide health problem that affects about
`1 to 2% of the population.l2"'l Despite progress in
`understanding the pathogenesis of seizures and ep-
`ilepsy,l25l the cellular basis of human epilepsy is
`only incompletely understood. In the absence of a
`specific aetiological understanding, approaches to
`drug therapy of epilepsy must necessarily be di-
`rected at the control ofsymptoms (i.e. the suppres-
`sion of seizures). Long-term administration of AEDS
`is the treatment of first choice in epilepsy.
`The selection of an AED is based primarily on
`its efficacy for specific types of seizures according
`to the international classification of epileptic sei-
`zures.l3‘5' The major categories within this classifi-
`cation a1'e partial and generalised seizures, based
`on whether a seizure be-gins locally in a part of one
`hemisphere. most commonly the temporal lobe,
`for partial seizures, or is bilaterally symmetrical
`without local onset for generalised seizures. In ad-
`dition to this classification of seizures, various
`types of epilepsy or epileptic syndromes can be
`identified as characterised by different seizure
`types. aetiologies, age of onset and EEG fcattrres.l3“l
`More than 40 distinct epileptic syndromes have
`been identified. making epilepsy a remarkably di-
`verse collection of disorders. Localisation-related
`
`O Adls Irnerncrtlonol Limited. All rlg his reserved.
`
`CNS Drugs 2002; lo (10)
`
`Page 5 of 28
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`Page 5 of 28
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`

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`(focal, local, partial) epilepsies account for roughly
`60% of all epilepsies, while generalised epilepsies
`account for approximately 40% of all epi1epsies.l3“l
`An epilepsy or epileptic syndrome can be idio-
`pathic (with a presumed genetic basis). symptomatic
`(i.e. secondary to a known acquired brain pathol-
`ogy) or cryptogenetic (without a known causation).
`Known potential causes of epilepsy account for
`about one-third of incidences of epilepsy and in-
`clude brain tumours, CNS infections. traumatic
`head injuries. developmental malformations, peri-
`natal insults. cerebrovascular disease, febrile sei-
`zures and status epilepticusml
`
`4. Animal Models of Epilepsy
`
`In epilepsy research, animal models of epilepsy
`or epileptic seizures serve a variety of purposes.l35l
`First, they a1'e used in the search for new AEDs.
`Second. once the antieonvulsant activity ofa novel
`compound has been detected, animal models are
`used to evaluate the possible specific efficacies of
`the compound against different types of seizures or
`epilepsy. Third, animal models can be used to char-
`acterise the preclinical efficacy of novel com-
`pounds during long-term administration. Such
`long-term studies can serve different objectives,
`for instance evaluation of whether drug efficacy
`changes during prolonged treatment (e.g. because
`ofthe development oftole1'ance) or examination of
`whether a drug exerts antiepileptogenic effects
`during prolonged administration (ie. is a true AED).
`Fourth, animal models are employed to charac-
`terise the mechanism of action of older and newer
`AEDS. Fifth. certain models can be used to study
`mechanisms of drug resistance in epilepsy. Sixth.
`in view of the possibility that chronic brain dys-
`function, such as with epilepsy. might lead to al-
`tered sensitivity to drug adverse effects, models
`with epileptic animals are useful to study whether
`epileptogenesis alters the adverse effect potential
`of a given drug. Finally, animal models a1'e needed
`for studies on the pathophysiology of epilepsies
`and epileptic seizures (e.g. the processes involved
`in epileptogenesis and ietogenesis).
`
`The most commonly employed animal models =
`in the search for new AEDs are the maximal electro-
`
`shock seizure (MES) test and the pentylenetetrazole
`(PTZ) seizure test.l3“l The MES test, in which tonic
`hinrllimb seizures are induced by bilateral corneal
`or transauricular electrical stimuiation, is thought
`to be predictive ofanticonvulsant efficacy against
`generalised tonic-clonic seizures. In contrast. the ‘
`PTZ test, in which generalised myoclonie and cle-
`nic seizures are induced by systemic (usually sub-
`cutaneous) administration of convulsant doses of
`PTZ, is thought to represent a valid model for
`generalised absence andalor niyoclonic seizures in
`humans, but its predictive validity is far from ideal.
`Thus, as shown in table 1, although lamotrigine is
`ineffective in the PTZ test, it protects against ab-
`sence and myoclouic seizures in patients with epi-
`lepsy. Vigabatrin and tiagabine are effective in the
`PTZ test but not against absence or myoclonic sei-
`zures in patients. Genetic animal models such as
`lethargic (ll:/Hr) mice, which have behavioural and
`elcctrographic features similar to those of human
`absence seizures, are clearly better suited to predict
`AED efficacy against this type of nonconvulsive
`seizure than the PTZ testilsl
`In addition to these models of primary general-
`ised seizures, the kindling model is widely used as
`a model of partiai (focal) seizures. The kindling
`model has correctly predicted the clinical effect of
`all AEDS that are currently used against partial sei-
`zures (see table I).
`
`5. Effects in Experimental Models of
`Epilepsy and Epileptic Seizures
`
`Valproate exerts anticonvulsant effects in at-
`most all animal models of seizure states, including
`models ofdifferent types of generalised seizures as
`well as focal seizures.l3l Table 1 shows a compari-
`son of the effects of valproate with those of other
`AEDs in the MES, PTZ and kindling models, as
`well as in clinical seizures. As shown by this com-
`parison, the only other AEDs with a similar wide
`spectrum of activity as valproate a1'e the benze-
`diazepines. However, the use of the ben2odia.z—
`epines
`AE5Ds is limited because of the loss of
`
`to Adls International Limited. All rights reserved.
`
`CNS Drugs 2052.’ loflfll
`
`Page 6 of 28
`
`Page 6 of 28
`
`

`
`673
`B;1§,1C l)i"l€II'I1'1c‘.tCCll0g)«' of Valproate
`_
`
`Table I. Anticonuulsant effect of clinically established anliepileptic drugs (A EDs]« against ditlerenl types of seizures in the maximal eiectroshock
`seizure (MES), pentyienetetrazole (PTZ) and kindling models and in human epllepsyl”-3°‘
`Dmg
`Antlconvulsant activity in experimental models
`Clinical elficacy
`MES test
`PTZ test
`amygdala-kindling
`partial seizures
`(mice or rats,
`(mice or rats,
`test (rats. local
`tonic seizures}
`clonic seizures)
`seizures)
`+
`+
`+
`+
`NE
`+
`+
`NE
`+
`+
`+
`+
`
`generalised seizures
`tumcfllonic
`absence
`+
`+
`NE
`N E
`NE
`
`myflcionic
`+
`NE
`NE
`+
`
`+
`+
`+
`+
`
`Valproate
`Carbamazepine
`Phsnytoin
`Phenobarbital
`lphenobarbltonel
`+
`Primidone
`+
`-+
`+
`Benzodiazepinesa
`NE
`NE
`+
`Ethosuximide
`+
`+
`NE
`Lamotrigine
`+
`4-
`NE
`Topiramate
`4-
`'?
`1
`+
`Oxcarbazepine
`+
`+
`+
`+
`Felbamate
`+
`+
`+
`NE
`Vigabalrin
`+
`+
`+
`NE
`‘Fiagabine
`+
`+
`x
`i
`Gabapentin
`+
`+
`NE
`NE
`Levetlracetam
`+
`7
`i
`+
`Zonisamlde
`a Loss at etlicacy (Le. development of tolerance) durln lorig—term administration.
`NE = not effective; + indicates ettectlve; : indicates inconsistent data; '? indicates no data available (criminal.
`
`+
`+
`NE
`+
`
`+
`+
`NE
`+
`+
`+
`+
`‘?
`4-
`7
`?
`+
`
`NE
`+
`+
`+
`s
`'?
`1
`NE
`NE
`NE
`"
`+
`
`+
`+
`1
`+
`+
`‘?
`+
`NE
`NE
`NE
`9
`+
`
`efficacy during long—term treatment. No such loss
`of efficacy, and even an increase in efficacy,
`is
`seen during long-term treatment with valproate
`(see below).
`In animal models, the anticonvulsant potency of
`valproate strongly depends on the animal species,
`the type of seizure induction, the seizure type, the
`route of adrninistration and the time interval be-
`tween drug administration and seizure induc-
`tion.[3l Because of the rapid penetration into the
`brain but the short half-life of valproate in most
`species,D” the most marked effects are obtained
`shortly (i.e. 2 to 15 minutes) after parenteral (e.g.
`intraperitoneal) injection. Depending on the prep-
`aration, the onset of action after oral administra-
`
`tion may be somewhat retarded. In most laboratory
`animal species, the duration of anticonvulsant ac-
`tion of valproate is only short. so high doses of
`valproate are needed to suppress long-lasting or
`repeatedly occurring seizures in animal modelsfizl
`in general, the anticonvtilsant potency of valproate
`
`© Aclis lnternolion Ul Limited. All rights reserved.
`
`Page 7 of 28
`
`increases in parallel with the size ofthe animal. In
`rodents, the highest anticonvnlsant potcncies are
`obtained in genetically seizure-susceptible spe-
`cies. such as gerbils and rats with spontaneously
`occurring spike-wave discharges. and against sei-
`zures induced by the inverse benzodiazepirte re-
`ceptor agonist rnetltyl-6.7-diuretlioxy-4—eth_yl—|3—
`carboline-3—carboxylate (DMCM) in mice.[2l
`In addition to animal models of generalised or
`focal seizures, valproate also has been evaluated in
`models of status epilepticus. As shown by I-{ijnack
`and Ltischerlm in a mouse model of generalised
`convulsive (grand mal) status epilepticus, intrave-
`nous injection of valproate was
`rapidly acting
`as benzodiazepines in suppressing generalised
`tonic—clonic seizures, which was related to the in-
`stantaneous entry of valproate into the brain after
`this route of administration. In View of the differ-
`ent inechanisms presumably involved in the anti-
`convulsant activity of valproate against different
`seizure types, the situation may be different for
`
`CNS Drugs 2002: lo (lfl)
`
`Page 7 of 28
`
`

`
`other types of status epilepticus, because not all
`cellular effects of valproate occur rapidly after ad-
`ministration. This is substantiated by accumulating
`clinical experience with parenteral formulations of
`valproate in the treatment of different types (eg.
`convulsive vs noncouvulsive) of status epilepti-
`cus.l33l
`
`5.] Early versus Lctte Effects
`
`Whereas most reports dealing with the anticom-
`vulsant activity of valproate in animal models ex-
`amined the acute short-lasting anticonvulsant ef-
`fects after single—dose administration. several
`stttdics have evaluated the anticonvnlsant efficacy
`of the drug during long-term administration. Dur-
`ing the first days oftreatrnent of amygdala-kindled
`rats, a marked increase in anticonvulsant activity
`was observed, which was not related to alterations
`in brain or plasma drug or metabolite concentra-
`tions.l-ii‘-“"l Similarly, when anticonvulsant activity
`was measured by means oftimed intravenous infu-
`sion of PTZ, prolonged treatment of mice with
`valproate resulted in marked increases in anticoa-
`vulsant activity on the second day oftreatment and
`thereafter compared with the et'fect of a single
`dose. although plasma concentrations measured at
`each seizure threshold determination did not differ
`
`signit'icai1tly.l35l This ‘late effect‘ of valproate de-
`veloped irrespective ofthe administration protocol
`(once per day, three times per day. continuous in-
`fusion) used. Such an increase in anticonvulsant
`activity during l0rtg~tcrn1 treatment was also ob-
`served in patients with epiIepsyl'5l and should be
`considered when single anticonvulsant doses or
`concentrations of vaiproate in animal models are
`compared with effective doses or concentrations in
`patients with epilepsy during long-term treatment.
`In other words. doses or plasma concentrations be-
`ing ineffective after single—dose administration can
`becotne el't'ective during long-term administration.
`The possible mechanisms involved in ‘early’ (i.e.
`occurring immediately after first administration of
`an effective dose) and ‘late’ (Le. developing during
`long-term administration) anticonvulsant effects
`of valp1'oate will he discussed in section 8. In this
`
`respect, it is important to note that early and late
`effects of valproate also have been observed in in
`wtro prepat'atiotis.l"“-3”
`
`5.2 Antiepileptogenic oocl
`Neuroprotective Effects
`
`In addition to short— and long—term anticonvul-
`sant effects in animal models of seizures or epi-
`lepsy, data from the kindling model indicate that
`valproate may exert antiepileptogenic effects.l3“l
`In line with this possibility, valproate protected
`against the development of epilepsy in the kainate
`model oftemporal lobe epilepsy, in which sponta-
`neous recurrent seizures develop after a status
`epilcptieus induced by the convulsant lcainate in
`i'ats.l39l Phenobarbital was ineffective in this re-
`
`gard.l3°l Whether valproate can prevent epilepsy
`after a convulsive status epilepticus in humans is
`not known, but it failed to prevent epilepsy after
`severe head injury.l‘“l
`Interestingly, valproate not only prevented the
`development of epilepsy in the kainate model of
`temporal
`lobe epilepsy in rats, but valproate—
`treated rats also had fewer histological brain le-
`sions than animals receiving kainate alone, indicat-
`ing that valproate exeits a neuroprotective effect.l-ml
`Substantiating such an effect. valproate was shown
`to protect cortical neurons from glutamate-induced
`excitotoxicity,l‘“l human SYSY neuroblastoma cells
`from potassium efflux—induced cell damage and
`apoptosis,l“'-'1 and cerebellar granule cells from
`apoptosis induced by low potassium.l“3l A neuro-
`protective effect of valproate is also indicated by
`the finding that the drug doubles the anoxic sur-
`vival time of n1ice.l““l Valproate regulates a num-
`ber of factors involved in cell survival pathways,
`including cyclic adenosine monophospltate (CAMP)
`responsive element binding protein (CREE), brain-
`derived neurotropliic factor, bcl—2 and rnitogen—
`activated protein kinases (MAP), which may underlie
`its neuroprotective and neurotrophic effects.l4-‘J
`
`5.3 Procortvulsont Effects
`
`Certain AEDs ma
`
`irovoke aradoxical seizure
`P
`Y I
`aggravation by a pharmacodynaniic mechanism.l“"l
`
`’-it Adis Inte motlonol Llmlletd. All rights reserved.
`
`CNS Drugs 2ou2.- lb tin)
`
`Page 8 of 28
`
`Page 8 of 28
`
`

`
`675
`Basic Pharniacology of Valproate
`
`
`Such proconvulsant action occurs when an AED
`appears to exacerbate a type of seizure against
`which it is usually effective or when it leads to the
`onset of new types of seizures. This unpredictable
`procoitvulsant adverse effect usually occurs shortly
`after the onset of treatment with the AED at non-
`
`toxic doses. Even at high, stipiatlierapeutic doses,
`valproate does not induce any proconvulsant activ-
`ity.i2l This is in Contrast to several other AEDS,
`including pheiiytoin, carbatnazepine and vigabati-in,
`which, at high doses, exert proconvulsant activity
`in animal models attd can precipitate or exacerbate
`epileptic seizures in patients with epilepsy.l4(’]
`
`5.4 Other Phorrnocodyncimic Effects
`
`In addition to its anticonvulsant activity, val-
`proate exerts several other phanriacodynamic effects
`in animal models, including anxioiytic, antiaggresr
`sive. anticonfliet, antidystonie, antinociceptive.
`sedative/hypnotic, immunostimulating and antihy—
`pertensive actions.[3l Several of these preclinical
`actions are in line with the therapeutic potential of
`valproate in indications other than epilepsy.“-2-‘”'
`
`5.5 Phorrncicoklnetic orid
`
`Phcirmcicodynomic Issues
`
`The ‘active’ concentrations of valproate in the
`brain or plasma strongly depend on the model ex-
`amined. When a valpr0ate—sensitive model, such
`as the threshold for clonic seizures determined by
`intravenous infusion of PTZ in mice, is used. the
`drug concentrations in brain tissue after adminis-
`tration of effective doses are near the range of ef-
`fective concentrations determined in brain biop-
`sies of patients with epilepsy, which are in the
`range of 40 to 200 ttmol/L. (table II).i3l However,
`it should be noted that because of the marked dif-
`
`ferences in pharmacokinetics of valproate between
`rodents and humans {rodents eliminate valproate
`about ten times more rapidly than humansm), the
`doses that have to be administered to reach these
`brain concentrations in mice or rats are much
`
`higher than respective doses iit humans. Such de-
`terminations of effective brain concentrations are
`
`important for interpretation of in uitro data on
`
`valproate, since the neurochemical or neurophysi-
`ological effects of valproate found in vt'2‘ro are only
`of interest if they occur in concentrations that are
`reached in vivri at anticonvulsant (nontoxic) doses.
`Because valproate is rapidly metabolised to var-
`ious pharmacologically active metabolites in
`irr'vo,l49l these substances have to be cottsidered
`when mechanisms of action of vaiproate are dis-
`cussed. One of the major active metabolites of
`valproate in the plasnta and CNS of different spe-
`cies, ineluding humans, is the i‘i"CH‘.'.\" isomer of 2-
`en-valpi'oate (E-2-en—valproate). This compound
`is the most potent and most extensively studied
`active metabolite of valproate.”-5°-5'l Ti‘cms-2-en-
`valproate is effective in the same seizure models
`as valproate, often with higher potency than the
`parent drug. Accordingly, in most neurochemical
`and neurophysiological experiments with tr.:tn.r-2-
`en-vaiproate. the compound exerted more potent
`effects than valproatenizl However, the brain con-
`centrations of ti-ans-2—en—valpt'oate occurring after
`administration of valproate in different species in-
`cluding humans are mtich too low to be of any
`significance for the effects of valproate.i3i
`There are a number of interesting pharrnacody-
`namic interactions between v