New Antileptic Agents

7/27/2019 New Antileptic Agents

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Se izu re 1 9 9 5 ; 4 : 5 -1 7

N e w a n t ie p i le p t ic d r u g s m a n e x p l o s io n o f a c t iv it yJOHN PAUL LEACH & MARTIN J. BRODIEEp i le p s y Re s e a rc h U n i t, Un iv e rs i t y De p a r tme n t o f Me d ic in e a n d T h e ra p e u ti c s, W e s te rn In fi rma ry , G la s g o w,Sc o t la n d , UKCorresponden ce to: Dr Mart in J. Brodie, Epi lepsy R esearch U ni t , Department of Medicine and Therapeut ics, We stern Inf i rmary,G lasgow G11 6N T, Scot land, UK.

The low the rapeut ic index of e s tab l i shed an t iep i lep t ic drugs coupled wi th a be t te r und ers tand ing of thepa thophys io logy of se izure produc t ion has led to the deve lopm ent of a r a nge of new th e rapeu t ic agents for thet rea tm en t of ep i lepsy . In th is r ev iew, the three drugs r ecen t ly licensed in the U K (v igaba t r in , lam otr ig ine andgabapen t in) a re prof iled , tog e the r wi th seve ra l o f the mo re promis ing up-and-coming cofi lpounds (oxca rbaze -p ine , f e lbamate , t iagabine , s t i r ipento l , r emac em ide and top i ram ate ) . Futu re av enues for cl in ical r e sea rch inthe pha rm acologica l m anag em ent of the ep i leps ies involve the i r r a t iona l use both s ing ly and in com bina t ion .Key words: antiep ileptic drugs; epilepsy; interaction s; neurop harm acolo gy; side-efects.

INTRODUCTIONE p i l e p s y i s a c o m m o n c o n d i ti o n w i t h a p o i n tp r e v a l e n c e o f j u s t u n d e r 1 % o f a g i v e n p o p u -l a t i o n 1. T h e r e a r e , b y i m p l i c a t i o n , a r o u n d5 0 0 0 0 0 p e o p l e in t h e U K a l o n e w h o h a v e e p i -l e p ti c s e i z u re s , f e w e r t h a n 7 0 % o f w h o m w i l lh a v e t h e m f u l ly c o n t ro l le d w i t h t h e c u r r e n t l ya v a i l a b l e a n t i e p i l e p t i c d r u g s 2. M a n y p a t i e n t s ,p a r t i c u l a r l y t h o s e w i th u n d e r l y i n g a n a t o m i c a ll e si o n s , re s p o n d p o o r l y t o m o n o t h e r a p y a n d a r et r e a t e d w i t h c o m b i n a t io n s o f a n t ic o n v u l s a n t st h a t o f t e n c a u s e d i s a b l i n g s i d e -e f fe c t s w i t ho n l y a n o u t s i d e c h a n c e o f s ig n i f i c a n t l y im -p r o v e d s e i z u r e c o n t r o l .

D o s e - r e l a t e d s i d e - e f f e c t s a n d i d i o s y n c r a t i cr e a c t i o n s a r e a l l to o c o m m o n w i t h e x i s t i n ga n t i c o n v u l s a n t s . T h e t e n d e n c y t o p r o d u c eh e a d a c h e , n a u s e a , d i z zi n e ss , d r o w s i n e s s , c o g ni -t i v e i m p a i r m e n t a n d o t h e r c e n t r a l n e r v o u ss y s t e m s i d e -e f fe c t s i s a l m o s t u n i v e r s a l 2. T h e i rp o t e n t i a l f o r t e r a t o g e n i c i t y 3 ' 4 a n d f o r d e l e t e r i -o u s d r u g i n t e r ac t i o n s 5 m a k e t h e i r l o n g - te r mu s e p r o b l e m a t i c a l . T h e l a s t f e w y e a r s h a v eb e e n e x c i t i n g t i m e s f o r e p i l e p t o l o g i s t s . T h e r eh a s b e e n a r u s h o f i n t e r e s t i n g n e w a n t i e p i l e p -t i c d r u g s i n t o c l i n i c a l d e v e l o p m e n t .

THE BASIS OF SEIZURESH i s t o l o g i c a l l y , e p i l e p t i c n e u r o n a l t i s s u e o f t e ns h o w s o n l y n o n - s p e c i fi c c h a n g e s s u c h a s g l i o s iso r d e n d r i t i c d e g e n e r a t i o n 6 '7 . T h e b i o c h e m i c a li n t e r p l a y a t t h e s i t e o f e p i l e p t o g e n e s is i s m o r ei n t e re s t i n g , a n d a n u n d e r s t a n d i n g o f t h ep a t h o g e n e s i s m a y l e a d u s t o a l t e r s u c c e s s f u l l yt h e s u b t l e b i o c h e m i c a l i m b a l a n c e s r e s p o n s i b l ef o r s e i z u r e g e n e r a t i o n a n d p r o p a g a t i o n . R e c e n ta d v a n c e s i n d r u g d e v e l o p m e n t h a v e f o c u s e d o nt h e t h e r a p e u t i c p o t e n ti a l o f m a n i p u l a t i n gb r a i n n e u r o t r a n s m i t t e r s .

E n d o g e n o u s s u b s t a n c e s su c h a s g a m m a a m i -n o b u t y r i c a c id ( G A B A ) , a d e n o s i n e a n d g l y c i n ea r e t h o u g h t t o b e o f i m p o r t a n c e i n i n h i b i t i n gs e i z u r e s p r e a d 7. S t i m u l a t i o n o f t h e G A B A Ar e c e p t o r r e s u l t s i n a n i n f l u x o f c h l o r i d e i o n s ,s t a b i l i z i n g t h e n e u r o n a l m e m b r a n e a n d p r e -v e n t i n g s e i z u r e ac t i v i ty . W o r k i n p r i m a t e s h a sd e m o n s t r a t e d a s e l e c t i v e lo s s o f s u c h t e r m i n a l si n e p i l e p t o g e n i c f o c is , i m p l y i n g a l o c a l d e f i c i t i ni n h i b i t i o n . T h e r e i s d e c r e a s e d b i n d i n g , a l so , t ot h e G A B A / b e n z o d i a z e p i n e r ec e p t o r c o m p l e x int e m p o r a l l o b e l e s i o n s 9.

T h e r o l e o f t h e e x c i t a t o r y a m i n o a c id s , e s-p e c ia l ly g l u t a m a t e a n d a s p a r t a te , h a s b e e nw e l l r e c o g n i z e d fo r a n u m b e r o f y e a r s . R e c e p -t o r s f o r t h e s e a n d o t h e r d i c a r b o x y l i c a c i d s a r ep r e s e n t i n a l t e r e d d e n s i t y i n p a t i e n t s w i t h1059-1311/95/010005 +04 $08-000 ~) 199 5 Bri tish Epi lepsy Associat ion


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6T a b l e 1 P h a r m a c o l o g i c a l p ro f i le o f a r a n g e o f n e w a n t i e p i le p t i c d r u g s

J . P . L e a c h & M . J . B r o d l e

Drug Mode of action Half life Elim inat ion Concentrat ions Effect on other(hours) affected by .. . AEDsFelbamate ? Glycine antagonist 14-22at NMDA receptorGabapent in ? Inhib ition of L-amino 5-7

acid transportLamotrigine Blocks Na channel s 25-29decreasing EAAreleaseRemacemide Non-competitiveNMDA antagoni st 3- 5(metabolite12-18)Stiripentol ? Inhibition of GABA Variableuptake and (saturationmetabolism kinetics)Tia gabine Decreases GABA 4-13reuptakeTopiramate Unknown 18-23Vigabatrin Decreases GABA 5-7

metabolism

Hepatic metabolism, Enzyme inducers PHT, VPA 1'some rena l excretion CBZRenal excretion Nil NilHepatic glucuroni- Enzyme inducers CBZdation and inhibi tors (pharmacodynamicinteraction)Hepatic metabolism Enzyme inducers PHT, CBZ, T(active metabolite) and inhibi torsHepatic metabolism Enzyme inducers PHT, CBZ, PBand inhibitorsHepatic metabolism ? Nil ? NilRenal excretion, some Unknow n Unknownhepatic metabolismRenal excretion Nil PHT

NMDA, n-methyl-D-aspar tate; EA_A, excitatory amino acid; AED, anti epil ept ic drugs; GABA, gamma aminobutyr ic acid;PHT, phenytoin; VPA, sodium valproate; CBZ, carbamazepine; PB, phenobarbitone.

e i t h e r g e n e r a l i z e d 1 o r t e m p o r a l l o b e 11 s e iz -u r e s . T h i s i m p l i c a t e s t h e e x c i t a t o r y s y s t e m i np r o d u c i n g a m i c r o - e n v i r o n m e n t c o n d u c i v e t oe p i l e p t o g e n e s i s . T h e s e p r o c e s s e s a n d t h e i ri n t e r p l a y a r e i m p o r t a n t f a ct o rs i n d e t e r m i n i n gt h e e x t e n t o f t h e n e u r o l o g i c a l i n s t a b i l i t yu n d e r l y i n g t h e i c t al d i a t h e s i s 12.

ESTABLISHED ANTICONVULSANTST h e l a s t t w o f i r s t - l i n e a n t i c o n v u l s a n t s t o b ei n t r o d u c e d i n t h e U K w e r e c a r b a m a z e p i n e i n1 9 6 7 a n d s o d i u m v a l p r o a t e i n 1 9 7 4. T h e s e a r es t il l t h e b e s t d r u g s f o r c o n t r o l l i n g m o s t t y p e s o fs e i z u re s . T h e r e r e m a i n s , h o w e v e r , a g r e a t d e a lo f s c o pe f o r i m p r o v i n g o u r t r e a t m e n t o f e p i-l e p sy . F e w e r t h a n 7 0 % o f p a t i e n t s a r e a d -e q u a t e l y c o n t r o l l e d w i t h a n t i e p i l e p t i c m o n o -t h e r a p y 13. T h e a d d i t i o n o f a s e c o n d o r t h i r dd r u g w i ll p ro v i d e s u b s t an t i a l i m p r o v e m e n t ino n l y a r o u n d 1 0% o f t h e r e m a i n d e r 2 . T h e m o r ea n t i e p i l e p t i c d r u g s t h e p a t i e n t t a k e s , t h eg r e a t e r t h e i n c i d e n c e o f a d v e r s e e f fe c ts , p a r -t i c u l a r l y c o g n i t i v e i m p a i r m e n t a n d t e r a t o g e -n e s i s .T h e m o d e s o f a c t i o n o f e s t a b l i s h e d a n t i e p i -l e p t ic d r u g s a r e , m u l t i p l e , c o m p l e x a n d o v e r l ap -p i n g T M . T h e i r e f f ec t s o n t h e c e n t r a l n e r v o u ss y s t e m a r e w i d e s p r e ad a n d r a t h e r i n d is c ri m i -n a t e - - a n e u r o p h a r m a c o l o g i c a l b l u n d e r b u s sr a t h e r t h a n a l as e r ! T h e i n t r o d u c t i o n o f t h r e en e w a n t i c o n v u l s a n t s w i t h n o v el m e c h a n i s m s o f

a c t i o n i n t h e U K o v e r t h e l a s t 5 y e a r s h a s r e v o -l u t i o n i z e d o u r a p p r o a c h t o r e f r a c t o r y e p i le p s y .V i g a b a t r i n , l a m o t r i g i n e a n d g a b a p e n t i n h a v el e d t h e w a y f o r a p l e t h o r a o f n e w e r a g e n t s t h a ta r e b e i n g e x t e n s i .v e l y t e s t e d i n s c i e n i f i c a l ly -b a s e d s t u d i e s w o r l d - w i d e.T h i s r e v i e w w i l l d e a l w i t h t h e c o m p o u n d st h a t a r e b r e a k i n g t h r o u g h i n t h e r o u t i n e m a n -a g e m e n t o f e p i le p s y , a n d w i l l fo c u s a ls o o n t h em o s t p r o m i s i n g d r u g s c u r r e n t l y u n d e r g o i n gc l i n i c a l t r i a l s . T h e p h a r m a c o l o g i c a l p r o f i l e s o ft h e a n t i c o n v u l s a n t s f e a t u r e d i n th i s p a p e r a r es u m m a r i z e d i n T a b l e 1 . T h e i r p o t e n t i a l r a n g e so f e f f i ca c y a r e o u t l i n e d i n T a b l e 2 .

NEW ANTIEPILEPTIC DRUGSVigabatrinV i g a b a t r i n w a s l i c e n s e d in t h e U K f o r u s e a sa d d - o n t h e r a p y f o r r e f r a c t o r y e p i l e p s y i n 1 9 8 9.I t i s b e i n g i n c r e a s i n g l y u s e d i n E u r o p e , A f r i c aa n d A s i a , b u t s t i l l a w a i t s r e g u l a t o r y a p p r o v a li n N o r t h A m e r ic a .

Mode of actionV i g a b a t r i n i s a G A B A a n a l o g u e w h i c h a c ts a sa ' s u ic i d e ' i n h i b i t o r o f G A B A - t r a n s a m i n a s e( F ig . 1 ). I t b i n d s i r r e v o c a b l y to i t s t a r g e te n z y m e , a n d s o f a c i l i t a t e s G A B A - e r g i c i n h i -


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New ant iep ilepUc drugsT a b l e 2 : E f f ic a c y o f a r a n g e o f n e w a n t i e p i le p t i c d r u g s a g a i n s t c o m m o n s e i z u r e t y p e s

P a r t i a l S e c o n d a r y g e n e r a l i z e d T o n i c - c l o n i c A b s e n c e M y o c l o n i cF e l b a m a t e + + ? ? ?G a b a p e n t i n + + ? - -L a m o t r i g i n e + + + + -I-O x c a r b a z e p i n e + + + - -R e m a c e m i d e + + ? ? ?S t i r i p e n t o l + + ? + ?T i a g a b i n e + + ? ~ ?T o p i r a m a t e + + ? ? ?V i g a b a t r i n + + ? - -

bition by interf ering with its catabolism is.Other possible modes of action have been alsosugges ted ~6.

P harm acok i ne t ic s and i n te rac ti onsVigabatrin is well absorbed after oral adminis-tration, with peak concentrations occurringaround 3 hours afte r dosing 17. Although it isgiven as a racemic mixture, only the S-enan-tiomer has a significant pharmacologicaleffect. The drug is excreted unchanged in theurine, with an elimi nation half-life of around 6hour s 17. Because of the irreversible action onits target enzyme, vigabatrin's pharmacologi-cal effect lasts longer than is suggested by itspharmacokinetics--perhaps as much as 48hour s 18. Vigabatr in is not s ignificant ly proteinbound, and does not induce or inhibit hepaticmetabolism. It decreases the phenytoi n concen-tration by around 20% by an unknown mech-anism 19. In only one (open) study has this beenthou ght to compromise seizure control2.

Ef f i cacy a nd to lerab i li t yMany studies have confirmed the efficacy ofvigabatrin as add-on therapy, particularly inpatients with partial seizures with or withoutsecondary generalization. On average, 50% ofpatients had thei r seizure frequency reducedby at least hal f 21. Its effect on general izedtonic-clonic seizures is variable, and it canexacerbate absences and myoclonic jerks.Tolerance is not thought to be a factor in itslong-term use, with efficacy demons trated forup to 7 years after initial administration22'23.Ther e appears to be a ceiling to effective dosingin individual p atients 24. For most, thi s occursaround 2 -3 g of vigabatrin daily25.A review of over 2000 patients on vigabatringave th e incidence of drowsiness at 10%, with

/f C

" !H 2 HG A B A // \

N H 2 V I G A B A T R I NF i g . I : S t r u c t u r e o f G A B A a n d v i g a b a t r i n .

OH

dizziness, headache, diplopia, ataxia and ver-tigo reported in approximately 2 % 2 1 . Toleranceto vigabatrin's sedative effects can beexpected26. Psychiatric problems following itsintroduction, such as anxiety, depression andaggression are well recognized. The precipi-tation of psychosis at high dosage or followingits sudden withd rawal cont raindicates vigaba-trin's use in patients with a his tory of behav-ioural disturbance21. Accordingly, initial dos-ing should be low (0.5-1 g daily) with carefultitration to a maximum of 2-3 g daily in themajor ity of patients 27.

Lamotr igineFolic acid was shown to have proconvulsantproperties in the mid-1960s. Accordingly, anti-epileptic drug development at the WellcomeInsti tute co ncentrated on folate antagonism asa method of identifying potential new antiepi-leptic drugs. Lamo trigine was born out of thissearch, although it is now known that theseproperties are not linked.

Mod e o f ac t ionLamotrigine is chemically and functionallyunrel ated to the other antiepileptic drugs (Fig.2). Its anticonvulsant effect arises from ablockade of sodium channels, limit ing the pre-synaptic release of glutamate and aspartate


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and, thus, stabilizing neuronal membranes2s.This, however, is unlikely to be the wholesto ry 29

Ph a r ma c o k in e t ics a n d i n te r a c t io n sOral ad ministra tion of lamotrigine leads to itsrapid and near complete absorption. The elim-ination half-life is around 29 hours withmetabolism largely by hepatic glucuronida-tion 3. Interestingly, patients with Gilbert'sdisease have a longer half-life due to a decreasein the activity of the enzyme bilirubin uridinediphosphate glucuronyl transf erase31.Lamotrigine does not itself induce or inhibithepati c enzymes. Consequently, it has no influ-ence on the metabolism of other lipid solubledrugs, including the oral contraceptive pill andwarfarin. Sodium valproate has been shown tolengthen its half-life to around 59 hours, andthe enzyme-inducing anticonvulsants, carba-mazepine, phenytoin and phenobarbitonereduce it to around 12 hours 32. There havebeen reports of symptoms of neurotoxicity(headache, nausea, dizziness, diplopia, ataxia)in patients taking carbamazepine in whomlamotrigine has been introduced33. These dis-appear when the dose of either drug is reduced.This is thought to be the clinical represen-tation of a pharmaco dynamic interaction34.

J.P. Leach & M.J. Brod leCl

~ ~ N,A .H 2 N N H 2

Fig. 2: Structure of lamo trigine.

Sedation is not a prominent manifestation oflamotrigine toxicity49.Double-blind trials to assess the usefulnessof lamotrigine as monotherapy, using carba-mazepine and phenytoin as comparators have

just been completed. Preliminary resultssuggest equal efficacy to carbamazepin e andphenytoin with better tolerability. Other com-parative studies in children, in the primarygeneralized epilepsies and in the elderly areunderway. The starting dose and titration ratewill depend on existing treatments when thedrug is used as adjunctive therapy (Table 3).Lamotrigine is usually prescribed twice daily,but a single daily dose can be used if the drug iscombined with sodium valproate or as mono-therapy. A low, slow introduction schedule willreduce the likelihood of rash.

Ef f icacy a nd to le rab i li tyTen double-blind, placebo-controlled, add-onstudies have been carried out with lamotri-gine35-44, nine of which reported successagainst partial seizures with or withoutsecondary generalization. Many open studieshave confirmed these findings4s. Clinical ex-perience also suggests that lamotrigine is ef-fective for the primary generalized epilep-sies 46. There is anecdotal evidence too tosupport its value in Lennox-Gastaut syn-drome47. These observations have not y et beensubst antiat ed in controlled clinical trials.Lamotrigine is a well-tolerated drug, withskin rash being the most common reason forwithdrawal. This occurs in approximately 3%of patients and depends on the rate of introduc-tion of the drug4s. Side-effects such as dizzi-ness, headache, nausea and vomiting, ataxia,diplopia and tremor are other minor problemsassociated with lamotrigine administration.

Table 3: Lamotr ig ine dos age and t i trat ion schedules1. Add-on in treated adults and adolescents

Weeks 1-2Weeks 3-4Maintenance

Valproate Other s25 mg alt die 50 mg daily25 mg daily 50 mg twicedaily50-10 0 mg twice 100-200 mg twicedaily daily2. Add-on in treated children

Valproate Other sWeeks 1-2 0.2 mg/kg 2 mg/kgWeeks 3- 4 0.5 mg/kg 5 mg/kgMaintenance 1-5 mg/kg 5-15 mg/kg3. Monotherapy in newly diagnosed epilepsy

A d u l t s C h i l d r enWeeks 1-2 25 mg daily 0.5 mg/kgWeeks 3- 4 25 mg twice 1 mg/kgdailyMaintenance 50-100 mg twice 2-8 mg/kgdailyH i g h e r d o s e s c a n b e t r i e d i f e i z u r e s p e r s is t a n d t h ep a t i e n t i s t o l e r a t i ng t h e d r u g w i t h o u t c o m p l a i n t .


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Gabapentin

H3N+ CO~[ I

Gabapentin, a chemical analogue of GABA,was intended to act as a GABA agonist (Fig. 3).It was thought too that, being hydrophilic,blood-brain barrier penetration would be fa-cilitated.

Fig. 3: St ructure of gabape nt in.

Mod e o f ac t ion

Oxcarbazepine

Interestingly, the anticonvulsant properties ofgabapentin are not dependent on any directaction on the GABA-ergic system51. The drugappears to bind to a membrane site near theglutamate receptor, which may represent atransport system for L-amino a c i d s 5 2 '5 3 . Arecent study suggests that gabapentin mayalso limit the rate of firing of sodium-depen-den t action potent ials 54.

gabapentin's efficacy against partial seiz-ures 5s. A clear-cut d ose-response relationshipin reducing partial and secondary generalizedseizures has been demonstrated with thedrug59. In a large double-blind, parallel group,placebo-controlled study involving 127patients with drug-resistant partial seizures,25% of these t aking gabapentin experienced areduction in seizure frequency exceeding50% 6. The the rapeut ic effect of gabapentinhas been shown to persist for up to 24mon ths 6~.Adverse events with gabapentin are gener-ally mild and transient62. The most commonare somnolence, fatigue, dizziness and weightgain. Other problems include diplopia, head-ache, ataxia and nausea. No idiosyncratic reac-tions have been reported to date. Early reportsare re assur ing also regardin g its lack of terato-genic potenti al 63.The recommended schedule for prescribinggabapentin involves thrice daily adminis-tration. However, some patients appear to re-spond to a morning and eveni ng dose. The drugshould be introduced over the first week at lowdosage (e.g. 300 mg twice daily) and th ere aft ercan be increased more rapidly as n ecessary to amaxi mum of 2700 mg daily or thereabouts. Itsuse is not curr ently recommended in childrenunder 12 years of age.

P harma cok i ne t ic s and i n te rac ti onsOral dosing of gabapentin results in rapidabsorption, and the drug has a bioavailabilityof 60%. A saturable transport mechanism inthe gut explains the lack of proportionality be-twe en increased doses and levels in plasma 55.Maximum concentrations occur 2-3 hoursafter administration and the elimination half-life approx imates 5-7 hours B6. There is no sig-nificant protein binding, and the drug isexcreted unchanged in the urine with clear-ance rates equivalent to those for creatinine.The lack of important drug interactions withgabapen tin has been widely reported57.

Ef f i cacy a nd to lerab i li t yA small, dose-ranging, double-blind cross-overstudy was the first to provide evidence for

0 / ' ~ NH2Fig. 4: Structure of oxcarbazepine.

Oxcarbazepine, the 10-keto analogue of carba-mazepine (Fig. 4), has been licensed for use in anum ber of countries worldwide. Its metabolismdiffers from that of the parent compound andthis holds out the possibility of a more benignside-effect profile with fewer drug interac-tions 64.

New ant lep ilepUc drugs


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1 0M o d e o f a c ti o nThe mode of action of oxcarbazepine is simila rbut not identical to that of carbamazepine65.Its major effect, therefore, is in preventingburst firing of neurones by blocking voltage-dependent sodium channels.

P h a r m a c o k i n e t i c s a n d i n t e r a c ti o n sOxcarbazepine is a pro-drug, the main activeprinciple being 10,11-dihydro-10-hydroxy-car-bamazepine which is largely eliminated byhepatic glucuronidation63. This moiety is 55%bound to.plasma proteins and has an elimin-ation half-life approximating 9 hours. Unlikecarbamazepine, oxcarbazepine does notundergo autoinduction of metabolism66. Thedrug has no effect on the metabolism of otheranticonvulsants67. However, the area underthe concentration-time curve of the activemetabolite is lower in patients taking carba-mazepine, phenytoin and phenobarbitone thanin controls suggesting a small, probably clini-cally irrelevant, induction effect of these drugson its elimination67'6s.Oxcarbazepine has less potential than carba-mazepine to induce liver enzymes and so influ-ence the metabolism of other drugs. It appearsto induce selectively a single isoform of cyto-chrome P450, na mel y IIIA 69. Volunteer studieshave suggested that it does not interfere withwarfarin metabolism7, nor will cimetidine71or dextropoxyphene72 inhibit its breakdown.However, decreased bioavailability of the oralcontraceptive pill has been noted in somepatients treated with oxcarbazepine73.

E f f i c ac y an d t o le r ab i l i tySeveral double-blind, add-on studies have con-firmed comparable efficacy between oxcarbaze-pine and carbamazepine74-76. In addition, nodifference in anticonvulsant effect was foundbetween oxcarbazepine and carbamazepine inpatients with n ewly diagnosed epilepsy77. Likecarbamazepine, oxcarbazepine has no place inthe treatment of absence seizures and myo-clonic jerk s 69.Comparisons with carbamazepine have sug-gested a lower incidence of minor side-effects7~-77. Those most commonly associatedwith oxcarbazepine are diplopia, nausea, head-ache, dizziness, drowsiness and atax ia 69.

J .P ." e a c h& M .J .Brod ieOxcarbazepine, like carbamazepine, has a pro-pensity to cause hyponatraemia in somepati ents 7s. However, it produces fewer rashesthan carbamazepine79 and perhaps other idio-syncratic reactions69.

Fe lbama te

Felbamat e is a dicarba mate derivative (Fig. 5)which is licensed in the United Sta tes and hasrecently gained approval for use in part ial seiz-ures and Lennox-Gastaut syndrome in someEuropean countries. It has been reported inanimal models as having an unique profile ofanticonv ulsant activity, with little tende ncy tocause neurotoxicity .

/ ~ / H = O C O N H =

C H = O C O N H =F i g .5 : S tr u c tu r e f e lb a m a t e .

M o d e o f a c t io nFelbamate has an interesting effect in de-creasing the binding of ligands at the glycinesite of the n-methyl-d-aspartate (NMDA)receptorsl. This implies that it may act as aglycine antagonist, possibly diminishing thedeleterious influence on neuronal function ofexcitatory amino acids. Several o ther modes ofaction have also been suggesteds2.

P h a r m a c o k i n e t ic s a n d i n t e ra c t io n sOral adminis tration of felbamate leads to com-plete and rapid absorption. Following a singledose, the half-life ranges between 14 and 22hours in epileptic pati ents s2. A proportion ofabsorbed drug is excreted unchanged in theurine, with the rest undergoing hydroxylationand conjugation in the liver.On addition of felbamate, phenytoin, val-proate and phenobarbitone levels will rise byaround 20-30%, whereas serum carbamaze-pine will fall by a similar amo unts3. However,this latte r effect is offset by gre ater productionof the active metabolite, carb amazepine 10,11


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N e w a n t i e p il e p t ic d r u g se p o x i d es 4 . E n z y m e - i n d u c i n g a n t i e p i l e p t i cd r u g s w i l l i n c r e a s e t h e r a t e o f c l e a r a n c e o f f e l-b a m a t e sS . T h e e f f e c t o f v a l p r o a t e o n f e l b a m a t el eve l s i s l e s s c l e a r - cu t s 6.

Ef f i cacy an d to lerab i li t yT h e e f fi c ac y o f f e l b a m a t e h a s b e e n e s t a b l i s h e di n s i x m a j o r c l in i c a l t r ia l s i n v o l v i n g a r o u n d3 7 0 p a t i e n t s 8 ~-92 . F i v e o f t h e s e w e r e u n d e r -t a k e n i n p a t i e n t s w i t h p a r t i a l s e i z u r e s w i t h o rw i t h o u t s e c o n d a r y g e n e r a l i z a t i o n . T h e f i n a lp i e c e o f e v i d e n c e c o n s i s t s o f a m a j o r p l a c e b o -c o n t r o l le d tr i a l i n 7 3 c h i l d r e n w i t h L e n n o x -G a s t a u t s y n d r o m e , ea c h o f w h o m h a d a t l e a s t9 0 a t o n i c o r a t y p i c a l a b s e n c e s e i z u r e s p e rm o n t h d e s p i t e t r e a t m e n t w i t h o n e o r t w oe s t a b l i s h e d a n t i e p i l e p t i c d r u g s . F e l b a m a t er e d u c e d t h e f r e q u e n c y o f a t o n i c s e i z u r e s a s w e l la s a t y p i c a l a b s e n c e s 9 . P r e l i m i n a r y r e s u l t s i nt h e p r i m a r y g e n e r a l i z e d e p i l e p s i e s a r e a l s op r o m i s i n g . L o n g - t e r m e f f i ca c y d a t a w i t h t h ed r u g , h o w e v e r , a r e s t il l l im i t e d , a l t h o u g h e a r l yo b s e r v a t i o n s a r e e n c o u r a g i n g93.T h e m o s t f r e q u e n t s i d e e f f e c t s w i t h f e l b a -m a t e o r i g i n a t e f r om t h e c e n t r a l n e r v o u ss y s t e m a n d i n c l u d e d i p l o p i a , d i z z i n e s s , h e a d -a c h e , n a u s e a a n d v o m i t i n g , d i a r r h o e a a n da t a x i a s2 . W e i g h t l o s s o f a r o u n d 5 % b o d y w e i g h th a s b e e n r e p o r t e d i n s o m e p a t ie n t s , p r o b a b l ys e c o n d a r y to a n o r e x i a a n d n a u s e a . B o t h i n s o m -n i a a n d s o m n o l e n c e h a v e b e e n a s s o c ia t e d w i t hf e l b a m a t e a d m i n i s t r a t i o n s3.

TiagabineT i a g a b i n e , a n i p e c o t i c a c i d d e r i v a t i v e ( F ig . 6 ),h a s a p o w e r f u l a n t i c o n v u l s a n t e ff e ct i n a n i m a ls e i z u re m o d e l s94.

s ,

" C H 3 H C IFig. 6: Struc ture of t iagabine.

11Mod e o f ac t ionT i a g a b i n e a c t s b y i n h i b i t i n g G A B A r e - u p t a k eb y g l i a l c e l l s a n d p r e s y n a p t i c n e u r o n e s 95. Ther e s u l t a n t i n c r e a s e i n s y n a p t i c G A B A c o n c e n -t r a t i o n s i s t h o u g h t t o b e r e s p o n s i b l e f o r i t sa n t i c o n v u l s a n t a c t i o n 96.

P harma cok i ne t ic s and i n te rac t ionsT i a g a b i n e i s w e l l - a b s o r b e d o r a l l y w i t h p e a kl e v e ls o c c u r r i n g a r o u n d a n h o u r a f t e r d o s i n g94.T h e e l i m i n a t i o n h a l f- li fe v a r i e s b e t w e e n 4 a n d1 3 h o u r s . E l i m i n a t i o n i s m a i n l y b y h e p a t i cm e t a b o l i s m , w h i c h a p p e a r s n o t t o b ei n f l u e n c e d b y c o n c o m i t a n t a n t i c o n v u l s a n tt r e a t m e n t .

Ef f i cacy an d to lerab i l i tyD o u b l e - b l i n d s t u d i e s s u g g e s t u s e f u l e f f ic a c y f o rt i a g a b i n e a g a i n s t p a r t i a l a n d s e c o n d a r y g e n e r -a l i s e d s e i z u r e s 9 7'9 s. M o n o t h e r a p y t r i a l s a r ea l s o c u r r e n t l y b e i n g u n d e r t a k e n 99. S i d e - ef f e c tss o f a r h a v e b e e n l a r g e l y c o n f i n e d t o h e a d a c h e ,d i z z i n e ss a n d s e d a t i o n .

RemacemideR e m a c e m i d e w a s d e s i g n e d t o a f fe c t t h e e x c it -a t o r y c o m p o n e n t o f e p il e p to g e n e s i s. I t h a sr e c e n t l y e n t e r e d p h a s e I I I c li n i c a l t r i a l s i n e p i -l e p t ic p a t i e n t s .

Mo de o f ac ti onR e m a c e m i d e is c h e m i c a l l y u n r e l a t e d t o a n yo t h e r a n t i c o n v u l s a n t ( F i g . 7 ) a n d h a s b e e ns h o w n t o b e a w e a k , n o n - c o m p e t i ti v e N M D Aa n t a g o n i s t 1 . A t l e a s t p a r t o f r e m a c e m i d e ' sa n t i c o n v u l s a n t a c t i o n i s t h o u g h t t o b e d u e t oi ts m a i n m e t a b o l i t e , th e d e s g l y c in a t e .

P harmaco k i ne t ic s and i n te rac t ionsO r a l d o s i n g of h e a l t h y v o l u n t e e r s s h o w sa b s o r p t i o n t o b e r a p i d , p e a k l e v e l s b e i n ga t t a i n e d a r o u n d 1 h o u r a f t e r a d m i n i s t r a t i o n .T h e p a r e n t d r u g h a s a n e l i m i n a t i o n h al f -l if ea p p r o x i m a t i n g 4 h o u r s , w h e r e a s t h e a c t i v ed e s g l y c i n a t e m e t a b o l i t e h a s a l o n g e r h a l f - li f e


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12 J.P. Lea ch & M.J. Brod i e

- - N

~ N H 2 H C IFig. 7: Structure of remacemide.i n t h e r e g i o n o f 1 2 - 1 8 h o u r s l . T h i s d i f f e r e n c ei n p h a r m a c o k i n e t ic s b e tw e e n p a r e n t d r u g a n da c t iv e m e t a b o l i t e is i m p o r t a n t i n d e t e r m i n i n gt h e o p t i m u m f r e q u e n c y o f d os in g .

T h o u g h n o t y e t c o m p l e t e , i n t e r a c t i o n ss t u d i e s w i t h r e m a c e m i d e s u g g e s t t h a t i t m a ya c t a s a n e n z y m e i n h i b i to r , s l o w i n g t h e m e t a b -o l i s m o f b o t h p h e n y t o i n a n d c a r b a m a z e p i n e ~1.C l e a r a n c e o f r e m a c e m i d e i s i n c r e a s e d i np a t i e n t s t a k i n g p h e n y t o i n a n d c a r b a m a z e p in ec o m p a r e d w i t h t h o s e tr e a t e d w i t h s o d i u m v a l -pro ate 12.

Eff ica cy an d to/erabi /i tyP r e l i m i n a r y r e s u l t s w i t h r e m a c e m i d e s u g g e s tu s e f u l e ff ic a c y a g a i n s t p a r t i a l a n d s e c o n d a r yg e n e r a l i z e d s e i z u r e s 1 3 '1 4 . I n c o m m o n w i t ho t h e r c e n t r a l ly a c t i n g d r u g s , li g h t h e a d e d n e s s ,d i p l o p i a a n d d i z z i n e s s h a v e b e e n r e p o r t e d a sw e l l a s g a s t r o - i n t e s ti n a l s y m p t o m s s u c h a sd y s p e p s i a , n a u s e a a n d v o m i t i n g . A g g r e s s i v eb e h a v i o u r h a s b e e n n o t e d o n r a r e o c c a s io n s . N oe v i d e n c e o f i d i o s y n c r a t i c r e a c t i o n t o t h e d r u gh a s s o f a r e m e r g e d .

Stiripentol

Mo d e o f a c t io nN o p r e c i se m e c h a n i s m o f a c ti o n h a s b e e n d e t e r -m i n e d , b u t l a b o r a t o r y s t u d i e s s u g g e s t t h a ts t i r i p e n t o l i n c r e a s e s G A B A l e v e l s e i t h e r b y i n -h i b i t i n g s y n a p t o s o m a l u p t a k e o r b y d e c r e a s i n gi t s m e t a b o l i s m l s

Ph a r ma c o k in e t ics a n d i n te r a c t io n sT h e d r u g i s s l o w l y d i s t r i b u t e d r e n d e r i n g i t se l i m i n a t i o n c u r v e m u l t i p h a s i c . I t i s h i g h l y p r o -t e i n b o u n d a n d u n d e r g o e s n o n - l i n e a r k i n -e t i c s 1 9 . S t i r i p e n t o l i s b i o t r a n s f o r m e d m a i n l yb y h e p a t i c m e t a b o l i s m H , a n d t h i s c a n b e a c -c e l e r a t e d b y o t h e r a n t i e p i l e p t i c d r u g s 111. I ts t r o n g l y i n h i b i t s t h e m e t a b o l i s m o f o t h e r a n t i-c o n v u l s a n t s , c a u s i n g a r is e i n c o n c o m i t a n t p h e -n y t o i n , c a rb a m a z e p i n e , s o d i u m v a l p r o a t e a n dphenobarbi tone112,113

Eff ica cy an d to/erabi/ ityM o s t o f t h e s t u d i e s c a r r i e d o u t s o f a r h a v e b e e no p e n l a b e l d e s i g n i n p a t i e n t s w i t h p a r t i a l s e iz -u r e s w i t h o r w i t h o u t s e c o n d a r y g e n e r a l i z -a ti on111 ,114 . A p re l i m i na ry r ep o r t s up po r t s e f fi -c a c y i n c h i l d r e n w i t h a t y p i c a l a b s e n c e s 115.O v e r a l l , s t i r i p e n t o l i s w e l l t o l e r a t e d w i t h o n l ya t a x i a , n a u s e a , v o m i t i n g a n d l e t h a r g y c u r -r e n t l y c o m p l i c a t i n g it s c l i n ic a l u s e .

TopiramateT o p i r a m a t e ( F i g. 9 ) i s y e t a n o t h e r a n t i e p i l e p t i cc o m p o u n d , w h i c h i s s t r u c t u r a l l y d i s t i n c t fr o ma l l o t h e r c o m p a r a b l e d r u g s !

S t i r i p e n t o l ( F ig . 8 ) h a s b e e n s h o w n t o b e a n Oe f f e c ti v e a n t i c o n v u l s a n t i n m a n y a n i m a l s e iz - 7 ~ , Ou r e m o d e ls 15-1~. SO=NH2Y . .H" ~ ~ c - - c I c " ~ c / C C H 3- /

J . I I i o .. - o - I' ~ , " ~ ' ~ C H 3 C H 3Fig. 8: Structure of stir ipentol. Fig. 9: Structure of topiramate.


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Ne w ant iep i lept ic drugsMo de o f ac ti onA s w i t h m a n y o f t h e n e w a n t i c o n v u l s a n t s , t h i si s p r e s e n t l y u n c e r t a i n . O n e s t u d y s u g g e s t s t h a ti t m a y e n h a n c e G A B A - m e d i a t e d c h l o r i d e i o nin f lu x l l6 .

P harmacok i ne t i c s and i n te rac t ionsT o p i r a m a t e i s s l o w l y a b s o r b e d a f t e r o r a l d o s-i n g , p e a k c o n c e n t r a t i o n s i n p l a s m a o c c u r r i n gb e t w e e n 1 a n d 4 h o u r s a f t e r a d m i n i s t r a t i o n .T h e d r u g i s e x c r e t e d l a r g e l y u n c h a n g e d i n th eu r i n e , w i t h a n e l i m i n a t i o n h a l f - li f e r a n g i n gf ro m 1 9 t o 2 3 h o u r s 11~ . A r o u n d 5 ~ o f a d o s eu n d e r g o e s h e p a t i c m e t a b o l i s m . I n t e r a c t i o n sw i t h o t h e r a n t i c o n v u l s a n t s h a v e s t i ll t o b ef u l l y d e l i n e a t e d .

Ef f i cacy an d to lerab i li t yA n u m b e r o f d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e ds t u d i e s h a v e b e e n c o m p l e t e d w i t h t o p i r a m a t ei n a d u l t s w i t h r e f r a c t o r y p a r t i a l s e i z u r e s w i t ho r w i t h o u t s e c o n d a r y g e n e r a l i z a t i o n ~ ls '~ mT h e s e h a v e s h o w n a g oo d r e s p o n s e ( d e f in e d a s ar e d u c t i o n o f > 5 0 c~ i n s e i z u r e f r e q u e n c y ) i nm o r e t h a n h a l f o f t h e p a t i e n t s t a k i n g m o r et h a n 2 0 0 m g o f t h e d ru g p e r d a y ~2" v ~l. P r e l i m i -n a r y d a t a a l so s u g g e s t e f fi c ac y i n th e L e n n o x -G a s t a u t s y n d r o m e ~2'~. T o p i r a m a t e a p p e a r sl i k e l y to b e a v a l u a b l e a d d - o n t r e a t m e n t i nr e f r a c t o ry e p i l e p s y ~23.T h e m o s t f r e q u e n t l y r e p o r t e d s i d e - e f f e c t sw i t h t o p i r a m a t e i n c lu d e a t a x i a , c o g n i t i v e d y s -f u n c t i o n , d i z z i n e s s , h e a d a c h e , n a u s e a , n y s t a g -m u s , t r e m o r a n d v i s u a l d i s t u r b a n c e . L e s sc o m m o n p r o b l e m s i n c l u d e m o o d l a b i l i t y a n dw e i g h t l o s s . A n i m a l t o x i c i t y s t u d i e s s u g g e s tt h a t t o p i r a m a t e m a y b e te r a t o g e n ic .

CONCLUSIONST h e r e c e n t d e v e l o p m e n t s i n t h e p h a r m a c o t h e r -a p y o f e p i l e p s y a r e p r o v i d i n g f o r m i d a b l e c h a l -l e n g e s t o t h e c l i n ic i a n . W h i c h p a t i e n t s s h o u l dr e c e i v e w h i c h d r u g a n d f o r w h i c h s e i z u r e t y p e ?S o fa r , m o s t is k n o w n a b o u t l a m o t r i g i n e a n dv i g a b a t r i n , a s th e s e h a v e b e e n i n g e n e r a l u s ef o r s o m e ye a r s . F e l b a m a t e a n d g a b a p e n t i nh a v e b e e n l i c e n s e d m o r e r e c e n t l y i n t h e U S Aa n d a p p r o v e d f o r l i c e n s i n g i n s o m e E u r o p e a nc o u n t r i e s . O x c a r b a z e p i n e , a l s o g e n e r a l l y a v a i l -

13a b l e i n s o m e c o u n t r ie s , a p p e a r s t o b e b e t t e rt o l e r a t e d t h a n c a r b a m a z e p i n e . T h e s e d r u g s a r eu n d o u b t e d l y v a l u a b l e in t h e t r e a t m e n t o fr e f r a c t o r y e p i l e p s y . T h e e a r l y c l i n i c a l p r o m i s eo f t i a g a b i n e a n d r e m a c e m i d e a r e i n d i c a t or st h a t t h e s e c o m p o u n d s t o o w i ll m a k e t h e t r a n -s i t i o n fr o m i n t e r e s t i n g c h e m i c a l s to u s e f u lt h e r a p e u t i c a g e n t s . S t ir i p e n to l a n d t o p i r a m a t es h o w a f e w m o r e p r o b l em s , b u t m a y w e l l p r o v ev a l u a b l e a s s e c o n d - l i n e t h e r a p y i n r e f r a c t o r ye p i l e p s y . T h e d r u g s t o u c h e d o n i n t h i s r e v i e wa r e m e r e l y t h e t i p o f a g r o w i n g i c e b e r g .

F o r a n a n t i e p i l e p ti c d r u g t o d e m o n s t r a t ee f f i ca c y in r e f r a c t o r y e p i l e p s y i s i m p r e s s i v e .T h e i r u s e a s a d j u n c t i v e t h e r a p y , h o w e v e r , i sl i k e l y t o e x a g g e r a t e t h e i r s i d e - e f fe c t pr o f il e s.T h e l e v e l p l a y i n g f i el d o f d o u b l e - b l i n d , c o n -t r o ll e d t r i a l s i n p r e v i o u s ly u n t r e a t e d p a t i e n t sw i ll d e m o n s t r a t e t h e t r u e w o r t h o f t h e s e n e wd r u g s i n c o m p a r i s o n w i t h t h e m u c h l e ss e xp e n -s i v e a n d m o r e e s t a b l i s h e d c o m p o u n d s . M o n o -t h e r a p y m a y w e l l p r o v e t h e n e w e r c r o p of a n t i-c o n v u l s a n t s m o r e b e n i g n . S o f a r , o n l yf e l b a m a t e h a s b e e n l i c e n s e d f o r t h i s i n d i c a t i o n ,a l t h o u g h l a m o t r i g i n e i s l i k e l y t o b e a v a i l a b l es o o n a s m o n o t h e r a p y i n E u r o p e .T h e u l t i m a t e g o a l f o r e v e r y o n e i n v o l v e d int h e d e v e l o p m e n t o f a n t i e p il e p t ic d r u g s i s t h ed i s c o v e r y o f e f f e c t i v e a n d s a f e a g e n t s w i t hw e l l -d e f in e d m e c h a n i s m s o f a c t io n . W e m a yf i n d i t a u s e f u l s t r a t e g y t o c o m b i n e d r u g s t h a ti n d e p e n d e n t l y i n f l u e n c e e i t h e r e x c i t a t o r y o ri n h i b i t o r y p r o c e s s e s . A s t i m e p a s s e s , t h e b e s tc o m b i n a t i o n s a r e l i k e l y t o b e d is c o v e r e d s e r e n -d i p i t o u s l y . T h e u s e o f t w o a g e n t s a c t i n g o n t h e' s a m e s i d e o f t h e f e n c e ' , s u c h a s v i g a b a t r i n a n dt i a g a b i n e , m a y b e a l o g ic a l a p p r o a c h i n r e f r a c -t o r y s i n g l e s e i z u r e t y p e s . T h o s e w i t h d i f f e r e n tm o d e s o f a c t i o n , s u c h a s v i g a b a t r i n a n d l a m o -t r i g i n e , m a y b e b e s t c o m b i n e d f o r p a t i e n t s e x -p e r i e n c i n g m o r e t h a n o n e s e i z u r e t y p e . A n a r -r o w e r r a n g e o f b i o c h e m i c a l e f f ec t s m a y l e a d t oe n h a n c e d t o l e r a b i l it y d u r i n g s u c h d u a l t he r -a p y , a n d ' s e l e c t i v e ' c o - p r e s c r i b i n g c o u l d b e t h ek e y t o i m p r o v i n g s e i z u r e c o n t r o l w i t h f e w e rs i d e e f f e c ts . T h i s a p p r o a c h s h o u l d s u p e r s e d et h e c u r r e n t e m p i r i c i s m , a n d l e a d t o t h er a t i o n a l e v o l u t i o n o f c o m b i n a t i o n t h e r a p y f o rt h e t r e a t m e n t o f r e f r a c t o ry e p i l e p sy .

ACKNOWLEDGEMENTO u r g r a t e f u l t h a n k s g o t o M r s M o y a D e w a r f o re x p e r t s e c r e t a r i a l a s s i s t a n c e .


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