REVIEW ARTICLE
`
`CNS Drugs 2002; 16 (10): 669-694
`1172-7047/02/0010-0669/$25.00/0
`
`© Adis International Limited. All rights reserved.
`
`Basic Pharmacology of Valproate
`A Review After 35 Years of Clinical Use for the
`Treatment of Epilepsy
`
`Wolfgang Löscher
`Department of Pharmacology, School of Veterinary Medicine, Toxicology and Pharmacy,
`Hannover, Germany
`
`Contents
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
`Abstract
`1. Historical Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
`2. Overview of Clinical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
`3. Epilepsy and Epileptic Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
`4. Animal Models of Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
`5. Effects in Experimental Models of Epilepsy and Epileptic Seizures . . . . . . . . . . . . . . . . . . . 672
`5.1 Early versus Late Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
`5.2 Antiepileptogenic and Neuroprotective Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 674
`5.3 Proconvulsant Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
`5.4 Other Pharmacodynamic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
`5.5 Pharmacokinetic and Pharmacodynamic Issues
` . . . . . . . . . . . . . . . . . . . . . . . . . 675
`6. Effects on Epileptiform Discharges in In Vitro and In Vivo Preparations . . . . . . . . . . . . . . . . 676
`7. Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
`7.1 Effects on Excitability or Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
`7.2 Effects on Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
`7.2.1 Sodium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
`7.2.2 Potassium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
`7.2.3 Calcium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
`7.3 Biochemical Effects
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
`7.3.1 Effects on the γ-Aminobutyric Acid (GABA) System . . . . . . . . . . . . . . . . . . . . . 681
`7.3.2 Effects on γ-Hydroxybutyrate, Glutamate and Aspartate . . . . . . . . . . . . . . . . . . 686
`7.3.3 Effects on Serotonin and Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
`7.3.4 Other Biochemical Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
`8. Possible Explanations for the Early and Late Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
`9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
`
`Abstract
`
`Since its first marketing as an antiepileptic drug (AED) 35 years ago in France,
`valproate 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 antiepileptic efficacy of valproate is reflected in
`preclinical in vivo and in vitro 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
`
`Ranbaxy Ex. 1020
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`

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`670
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`Löscher
`
`activity in epilepsy and other brain diseases. In view of the diverse molecular and
`cellular events that underlie different seizure types, the combination of several
`neurochemical and neurophysiological mechanisms 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 γ-aminobutyric acid (GABA) and thereby potentiates GABAergic functions
`in some specific brain regions thought to be involved in the control of seizure
`generation and propagation. Furthermore, the effect of valproate on neuronal
`excitation mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate
`receptors might be important for its anticonvulsant effects. Acting to alter the
`balance of inhibition and excitation through multiple mechanisms is clearly an
`advantage for valproate and probably contributes to its broad spectrum of clinical
`effects.
`Although the GABAergic potentiation and glutamate/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 γ-hydroxybutyrate
`(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 of action at therapeutically relevant concentrations
`in the mammalian brain is not clearly elucidated.
`By the experimental observations summarised in this review, most clinical
`effects of valproate can be explained, although much remains to be learned at a
`number of different levels about the mechanisms of action of valproate. In view
`of the advances in molecular neurobiology and neuroscience, future studies will
`undoubtedly further our understanding of the mechanisms of action of valproate.
`
`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.[1,2]
`Valproate is the trivial name for 2-n-propylpentanoic
`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.
`
`1. Historical Background
`
`Valproate was first synthesised in 1882 by Bur-
`ton,[3] but there was no known clinical use until its
`anticonvulsant activity was fortuitously discov-
`ered by Pierre Eymard in 1962 in the laboratory of
`G. Carraz, as published by Meunier et al.[4] At that
`
`time, valproate was used as a vehicle to dissolve
`the active ingredient in testing the anticonvulsant
`activity of new compounds.[5] 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 et al.,[6] and it was
`first marketed in France in 1967.
`
`2. Overview of Clinical Use
`
`Valproate has been used for the treatment of
`epilepsy for nearly 35 years and is currently mar-
`keted in over 100 countries. Since its introduction
`into clinical use, valproate has become established
`
`© Adis International Limited. All rights reserved.
`
`CNS Drugs 2002; 16 (10)
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`

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`Basic Pharmacology of Valproate
`
`671
`
`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 efficacy to ethosuximide in the
`treatment of absence seizures and to carbamaze-
`pine, phenytoin and phenobarbital (phenobarbi-
`tone) in the treatment of both tonic-clonic and par-
`tial seizures.[7-11] Furthermore, valproate compares
`favourably with newer AEDs, such as vigabatrin[12]
`and oxcarbazepine,[13] in both efficacy and toler-
`ability.[14]
`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.[15,16] In ad-
`dition to partial and generalised seizures, valproate
`has demonstrated efficacy in the treatment of syn-
`dromes known to be very refractory, such as
`Lennox-Gastaut syndrome[17,18] and West syn-
`drome.[19] This gives valproate special signifi-
`cance for the treatment of patients with mixed sei-
`zure types who have highly refractory symptoms.[14]
`Furthermore, as a consequence of its broad spec-
`trum of antiepileptic activity and as opposed to
`many other AEDs, there is no contraindication to
`the use of valproate in any type of seizure or epi-
`lepsy.[14]
`Valproate is tolerated well in most patients.[20]
`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.[20] Main areas of concern with valproate are
`teratogenicity 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 dose, have lowered this risk, so that with these
`recommendations valproate does not appear to in-
`duce birth defects with any greater frequency than
`other AEDs.[20] With respect to idiosyncratic liver
`toxicity, identification of high-risk patients such as
`
`children under 2 years with severe epilepsy and
`mental retardation receiving polytherapy has con-
`siderably reduced its incidence.[20]
`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
`and pharmacokinetics, several previous reviews
`and monographs are available.[1,2,15,21,22] Further-
`more, the major aspects of the clinical use of val-
`proate, its advantages and limitations and their cor-
`relation with pharmacological findings are covered
`in the review by Perucca[23]that also appears in this
`issue of CNS Drugs.
`
`3. Epilepsy and Epileptic Seizures
`
`Epilepsy, 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.[24] Despite progress in
`understanding the pathogenesis of seizures and ep-
`ilepsy,[25] 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 of symptoms (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.[26] The major categories within this classifi-
`cation are partial and generalised seizures, based
`on whether a seizure begins 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 features.[24]
`More than 40 distinct epileptic syndromes have
`been identified, making epilepsy a remarkably di-
`verse collection of disorders. Localisation-related
`
`© Adis International Limited. All rights reserved.
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`CNS Drugs 2002; 16 (10)
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`

`
`672
`
`Löscher
`
`(focal, local, partial) epilepsies account for roughly
`60% of all epilepsies, while generalised epilepsies
`account for approximately 40% of all epilepsies.[24]
`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 epilepticus.[27]
`
`4. Animal Models of Epilepsy
`
`In epilepsy research, animal models of epilepsy
`or epileptic seizures serve a variety of purposes.[28]
`First, they are used in the search for new AEDs.
`Second, once the anticonvulsant activity of a 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
`of the development of tolerance) or examination of
`whether a drug exerts antiepileptogenic effects
`during prolonged administration (i.e. 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 are needed
`for studies on the pathophysiology of epilepsies
`and epileptic seizures (e.g. the processes involved
`in epileptogenesis and ictogenesis).
`
`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.[28] The MES test, in which tonic
`hindlimb seizures are induced by bilateral corneal
`or transauricular electrical stimulation, is thought
`to be predictive of anticonvulsant efficacy against
`generalised tonic-clonic seizures. In contrast, the
`PTZ test, in which generalised myoclonic and clo-
`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 and/or myoclonic seizures in
`humans, but its predictive validity is far from ideal.
`Thus, as shown in table I, although lamotrigine is
`ineffective in the PTZ test, it protects against ab-
`sence and myoclonic 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 (lh/lh) mice, which have behavioural and
`electrographic 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 test.[28]
`In addition to these models of primary general-
`ised seizures, the kindling model is widely used as
`a model of partial (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 al-
`most all animal models of seizure states, including
`models of different types of generalised seizures as
`well as focal seizures.[2] Table I 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 are the benzo-
`diazepines. However, the use of the benzodiaz-
`epines as AEDs is limited because of the loss of
`
`© Adis International Limited. All rights reserved.
`
`CNS Drugs 2002; 16 (10)
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`
`Basic Pharmacology of Valproate
`
`673
`
`Table I. Anticonvulsant effect of clinically established antiepileptic drugs (AEDs) against different types of seizures in the maximal electroshock
`seizure (MES), pentylenetetrazole (PTZ) and kindling models and in human epilepsy[29,30]
`
`Drug
`
`Anticonvulsant activity in experimental models
`MES test
`PTZ test
`amygdala-kindling
`(mice or rats,
`(mice or rats,
`test (rats, focal
`tonic seizures)
`clonic seizures)
`seizures)
`+
`+
`+
`+
`NE
`+
`+
`NE
`+
`+
`+
`+
`
`+
`+
`+
`+
`
`Clinical efficacy
`partial seizures
`
`generalised seizures
`tonic-clonic
`absence
`
`myoclonic
`
`Valproate
`Carbamazepine
`Phenytoin
`Phenobarbital
`(phenobarbitone)
`+
`+
`+
`+
`Primidone
`Benzodiazepinesa
`+
`+
`+
`+
`NE
`NE
`+
`NE
`Ethosuximide
`+
`+
`NE
`+
`Lamotrigine
`+
`+
`NE
`+
`Topiramate
`±
`+
`?
`+
`Oxcarbazepine
`+
`+
`+
`+
`Felbamate
`+
`+
`+
`NE
`Vigabatrin
`+
`+
`+
`NE
`Tiagabine
`±
`±
`Gabapentin
`+
`+
`+
`+
`NE
`NE
`Levetiracetam
`±
`+
`Zonisamide
`+
`?
`a Loss of efficacy (i.e. development of tolerance) during long-term administration.
`NE = not effective; + indicates effective; ± indicates inconsistent data; ? indicates no data available (or found).
`
`+
`+
`+
`+
`
`+
`+
`NE
`+
`+
`+
`+
`?
`+
`?
`?
`+
`
`+
`NE
`NE
`NE
`
`NE
`+
`+
`+
`±
`?
`±
`NE
`NE
`NE
`?
`+
`
`+
`NE
`NE
`+
`
`+
`+
`±
`+
`+
`?
`+
`NE
`NE
`NE
`?
`+
`
`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 administration and the time interval be-
`tween drug administration and seizure induc-
`tion.[2] Because of the rapid penetration into the
`brain but the short half-life of valproate in most
`species,[31] 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 models.[2]
`In general, the anticonvulsant potency of valproate
`
`increases in parallel with the size of the animal. In
`rodents, the highest anticonvulsant potencies 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 benzodiazepine re-
`ceptor agonist methyl-6,7-diurethoxy-4-ethyl-β-
`carboline-3-carboxylate (DMCM) in mice.[2]
`In addition to animal models of generalised or
`focal seizures, valproate also has been evaluated in
`models of status epilepticus. As shown by Hönack
`and Löscher[32] in a mouse model of generalised
`convulsive (grand mal) status epilepticus, intrave-
`nous injection of valproate was as 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 mechanisms presumably involved in the anti-
`convulsant activity of valproate against different
`seizure types, the situation may be different for
`
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`CNS Drugs 2002; 16 (10)
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`674
`
`Löscher
`
`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 (e.g.
`convulsive vs nonconvulsive) of status epilepti-
`cus.[23]
`
`5.1 Early versus Late Effects
`
`Whereas most reports dealing with the anticon-
`vulsant activity of valproate in animal models ex-
`amined the acute short-lasting anticonvulsant ef-
`fects after single-dose administration, several
`studies have evaluated the anticonvulsant efficacy
`of the drug during long-term administration. Dur-
`ing the first days of treatment 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.[33,34] Similarly, when anticonvulsant activity
`was measured by means of timed intravenous infu-
`sion of PTZ, prolonged treatment of mice with
`valproate resulted in marked increases in anticon-
`vulsant activity on the second day of treatment and
`thereafter compared with the effect of a single
`dose, although plasma concentrations measured at
`each seizure threshold determination did not differ
`significantly.[35] This ‘late effect’ of valproate de-
`veloped irrespective of the administration protocol
`(once per day, three times per day, continuous in-
`fusion) used. Such an increase in anticonvulsant
`activity during long-term treatment was also ob-
`served in patients with epilepsy[15] and should be
`considered when single anticonvulsant doses or
`concentrations of valproate 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
`become effective during long-term administration.
`The possible mechanisms involved in ‘early’ (i.e.
`occurring immediately after first administration of
`an effective dose) and ‘late’ (i.e. developing during
`long-term administration) anticonvulsant effects
`of valproate will be 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
`vitro preparations.[36,37]
`
`5.2 Antiepileptogenic and
`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.[38]
`In line with this possibility, valproate protected
`against the development of epilepsy in the kainate
`model of temporal lobe epilepsy, in which sponta-
`neous recurrent seizures develop after a status
`epilepticus induced by the convulsant kainate in
`rats.[39] Phenobarbital was ineffective in this re-
`gard.[39] 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.[40]
`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 exerts a neuroprotective effect.[39]
`Substantiating such an effect, valproate was shown
`to protect cortical neurons from glutamate-induced
`excitotoxicity,[41] human SY5Y neuroblastoma cells
`from potassium efflux–induced cell damage and
`apoptosis,[42] and cerebellar granule cells from
`apoptosis induced by low potassium.[43] A neuro-
`protective effect of valproate is also indicated by
`the finding that the drug doubles the anoxic sur-
`vival time of mice.[44] Valproate regulates a num-
`ber of factors involved in cell survival pathways,
`including cyclic adenosine monophosphate (cAMP)
`responsive element binding protein (CREB), brain-
`derived neurotrophic factor, bcl-2 and mitogen-
`activated protein kinases (MAP), which may underlie
`its neuroprotective and neurotrophic effects.[45]
`
`5.3 Proconvulsant Effects
`
`Certain AEDs may provoke paradoxical seizure
`aggravation by a pharmacodynamic mechanism.[46]
`
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`CNS Drugs 2002; 16 (10)
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`Basic Pharmacology of Valproate
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`675
`
`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
`proconvulsant adverse effect usually occurs shortly
`after the onset of treatment with the AED at non-
`toxic doses. Even at high, supratherapeutic doses,
`valproate does not induce any proconvulsant activ-
`ity.[2] This is in contrast to several other AEDs,
`including phenytoin, carbamazepine and vigabatrin,
`which, at high doses, exert proconvulsant activity
`in animal models and can precipitate or exacerbate
`epileptic seizures in patients with epilepsy.[46]
`
`5.4 Other Pharmacodynamic Effects
`
`In addition to its anticonvulsant activity, val-
`proate exerts several other pharmacodynamic effects
`in animal models, including anxiolytic, antiaggres-
`sive, anticonflict, antidystonic, antinociceptive,
`sedative/hypnotic, immunostimulating and antihy-
`pertensive actions.[2] Several of these preclinical
`actions are in line with the therapeutic potential of
`valproate in indications other than epilepsy.[1,2,47]
`
`5.5 Pharmacokinetic and
`Pharmacodynamic Issues
`
`The ‘active’ concentrations of valproate in the
`brain or plasma strongly depend on the model ex-
`amined. When a valproate-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 μmol/L (table II).[2] 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 humans[2]), the
`doses that have to be administered to reach these
`brain concentrations in mice or rats are much
`higher than respective doses in humans. Such de-
`terminations of effective brain concentrations are
`important for interpretation of in vitro data on
`
`valproate, since the neurochemical or neurophysi-
`ological effects of valproate found in vitro are only
`of interest if they occur in concentrations that are
`reached in vivo at anticonvulsant (nontoxic) doses.
`Because valproate is rapidly metabolised to var-
`ious pharmacologically active metabolites in
`vivo,[49] these substances have to be considered
`when mechanisms of action of valproate are dis-
`cussed. One of the major active metabolites of
`valproate in the plasma and CNS of different spe-
`cies, including humans, is the trans isomer of 2-
`en-valproate (E-2-en-valproate). This compound
`is the most potent and most extensively studied
`active metabolite of valproate.[2,50,51] Trans-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 trans-2-
`en-valproate, the compound exerted more potent
`effects than valproate.[2] However, the brain con-
`centrations of trans-2-en-valproate occurring after
`administration of valproate in different species in-
`cluding humans are much too low to be of any
`significance for the effects of valproate.[2]
`There are a number of interesting pharmacody-
`namic interactions between valproate and other
`AEDs.[52] In animal models, valproate causes a
`supra-additive increase in the anticonvulsant ef-
`fects of phenytoin, carbamazepine, ethosuximide
`and felbamate without concomitantly increasing
`
`Table II. ‘Active’ concentrations of valproate in plasma and brain
`after administration of anticonvulsant doses to experimental ani-
`mals and patients with epilepsy. Plasma and brain concentrations
`in mice were determined after intraperitoneal administration of
`doses of valproate that increased the threshold for clonic pen-
`tylenetetrazole seizures by 50% (TID50).[2] Plasma and brain con-
`centrations in humans were determined during epilepsy surgery
`after oral treatment with antiepileptic doses of valproate[48]
`
`Doses of valproate
`(mg/kg) [route of
`administration]
`
`Mice
`
`Patients with
`epilepsy
`
`80-100
`[intraperitoneally]
`15-20 [orally]
`
`Concentrations of valproate
`plasma
`brain
`(μg/ml)
`(μg/g)
`[μmol/L]
`[μmol/L]
`120-150
`25-40
`[830-1040]
`[170-280]
`40-100
`6-27
`[280-690]
`[42-190]
`
`© Adis International Limited. All rights reserved.
`
`CNS Drugs 2002; 16 (10)
`
`

`
`676
`
`Löscher
`
`their toxicity, whereas lamotrigine and gabapentin
`potentiate the anticonvulsant efficacy of valpro-
`ate.[52]
`Consistent with the data from animal models, an
`enhancement of antiepileptic efficacy in patients
`with epilepsy was reported for combinations of
`valproate with carbamazepine, ethosuximide, felba-
`mate and lamotrigine.[52] However, the positive
`pharmacodynamic interaction between valproate
`and lamotrigine, which was first reported by Bro-
`die and Yuen,[53] is associated with an increased
`risk of lamotrigine-induced skin rashes.[54] This
`problem can be minimised when lamotrigine is
`added to valproate at very low initial doses.[55]
`In addition to pharmacodynamic interactions,
`valproate can affect the plasma concentrations of
`other AEDs, including lamotrigine, phenobarbital,
`phenytoin, ethosuximide and felbamate, by dis-
`placement from plasma proteins and/or inhibition
`of hepatic metabolism.[15] For instance, valproate
`can lead to 2- to 3-fold increases in the elimination
`half-life of lamotrigine (from 26 to 70 hours),
`which may at least in part explain the increased
`adverse effects seen with the combination of
`valproate and lamotrigine.[55]
`The precise mechanism of action of valproate
`or its active metabolites, as with many other AEDs,
`is unknown. Much attention has focused on the ef-
`fects of valproate on γ-aminobutyric acid (GABA),
`one of the principal inhibitory neurotransmitters in
`the CNS. However, given the various experimental
`and clinical effects of valproate and its numerous
`effects on neuronal tissue, there is no single action
`of valproate that can completely account for these
`effects.
`
`6. Effects on Epileptiform Discharges in
`In Vitro and In Vivo Preparations
`
`Various in vitro preparations were used to study
`the anticonvulsant action of valproate on epilepti-
`form discharges. In slices prepared from guinea pig
`brain, valproate was shown to prevent the appear-
`ance of penicillin-induced epileptiform spikes.[56]
`In contrast, valproate was either ineffective or
`caused an increase in both burst frequency and am-
`
`plitude when epileptiform activity was induced by
`PTZ in the CA3 region of the in vitro hippocampus,
`indicating that these chemically induced hippo-
`campal epileptiform activities may be differen-
`tially sensitive to AEDs.[57]
`Epileptiform bursting induced by bicuculline in
`rat amygdala slices was decreased by valproate.[58]
`When epileptiform discharges were induced by the
`combined application of bicuculline and 4-amino-
`pyridine (4-AP) in combined entorhinal cortex (EC)/
`hippocampal slices from rats, these discharges were
`resistant to valproate and other standard AEDs,[59]
`whereas epileptiform discharges induced by 4-AP
`alone were potently suppressed by valproate.[60]
`In studies on the age-dependency of the anticon-
`vulsant effect of valproate on 4-AP–induced epi-
`leptiform discharges in hippocampal slices, val-
`proate blocked the ictal discharges in slices from
`both young and adult rats, whereas interictal epi-
`leptiform activity was only blocked by valproate in
`slices from young rats.[61] In young rat hippocam-
`pus, extracellular magnesium was shown to mod-
`ulate the effects of valproate on 4-AP–induced ep-
`ileptiform events.[62]
`When epileptiform discharges were induced in
`the combined EC/hippocampal slice by removing
`magnesium ions from the perfusion fluid, early
`clonic-tonic discharges in the EC and