clobazam, oxcarbazepine, tiagabine, topiramate, and other new antiepileptic drugs

Epilepsia, 36(Suppl. 2):S105-SI 14, 1995 Raven Press, Ltd., New York 0 International League Against Epilepsy

Clobazam, Oxcarbazepine , Tiagabine, Topiramate, and Other New Antiepileptic Drugs

Robert Fisher and David Blum

Barrow Neurological Institute, St . Joseph’s Hospital and Medical Center, Phoenix, Arizona, U.S.A.

Summary: Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB rep- resent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium- channel antagonist. OCBZ is a keto analogue of carbamazepine, which is not metabolized to the epoxide and may

have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience. Key Words: Epilepsy-AnticonvulsantMlinical trials- Clobazam-Dezinamide-Flunarizine-Loreclezole- Milacemide-MK-801-Nafiknidone-Oxcarbazepine- Progabide-Ralitoline-S tiripentol-Tiagabine- Topiramate-Zonisamide-Adverse effects.

Patients with epilepsy and their caregivers are suddenly faced with a wide variety of new antiepileptic drugs (AEDs). At the time of this writing, two new AEDs [felbamate (FBM) and gabapentin (GBP)] have been introduced in the United States and 12 other AEDs are in clinical trial or awaiting marketing approval (Table 1). Several other medi- cations listed in Table 1 are in a holding pattern pending resolution of questions about safety or efficacy. Table 1 marks the 15 reviewed AEDs. Many other putative AEDs (not listed) are in phase 1 animal testing or in the process of moving from animal testing to patients, e.g., LO59 (Sharief et al., 1992) and losigamone (LSG) (Runge et al., 1993). Several new forms of old AEDs are also under study. This review includes the most important of the new AEDs that are not considered elsewhere in this volume. A few of the dormant AEDs are briefly de- scribed, because former patients or investigators may wonder what happened to them and because

Address correspondence and reprint requests to Dr. R. S. Fisher at Barrow Neuroloeical Institute, St. Joseoh’s Hosoital and Medical Center, 350-West Thomas Road, Phoenix,- AZ 85013496, U.S.A.

some may rise again under new license. AEDs are listed in alphabetic order.

CLOBAZAM (CLB)

Benzodiazepines (BZDs) are standard therapy for absence, tonic-clonic, myoclonic, and atonic seizures, but sedation and tolerance limit the utility of BZDs for long-term treatment. The most clinically useful BZDs in the United States are 1,Cnitro- genous ring structures. CLB is a 1,5-BZD (Allen et al., 1983) with a half-life of about 18 h and an active N-desmethyl metabolite with a half-life of 42 h (Remy, 1994). CLB is less sedating than clonaze- pam (CZP) (Wddin et al., 1990) and can be used as a single nocturnal dose. Whether patients tolerate CLB better than the other BZDs is under debate (Bardy et al., 1991). Carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) increase CLB levels (Sennoune et al., 1992). Conversely, CLB can precipitate PHT toxicity (Zifkin et al., 1991), and elevate the CBZ 10,ll-epoxide (CBZE) concentration in patients receiving CBZ (Muiioz et al., 1990).

CLB is an effective AED at dosages of 0.5-1.0 mglkglday (Buchanan, 1993). A meta-analysis by

Sl05

SIM R . FISHER AND D. BLUM

TABLE 1. New antiepileptic drugs

hug Company status

c~obazam" Dezinamide" Eterobarb Felbamate Flunarizine" Gabapentin Lamotrigine Loreclezole" M i m i d e " MK-801" Natihidone" ORG-6370" Oxcarbazepine" Phenytoin prodrug Rogabide" Ralitoline" Stiripentol" Tiagabine" Topiramate" V i a t r i n zonisamide"

Hoechst Athena Neurosciences MacroChem Carter-Wallace Janssen Parke-Davis Burroughs- Wellcome Jaossen Monsanto-Searle Merck Sharpe & Dohme Syntex Research Organon Scientific Ciba DuPont Pharmaceuticals Synthelo Pharmaceuticals Parke-Davis Biocodex Laboratory Abbott Pharmaceuticals RW Johnson & McNeil Marion MemU Dow We-Davis, Dainippon

Dormant Withdrawn In trial Marketed In trial Marketed Marketed In trial Withdrawn Stroke trials Donnant Dormant In trial In trial In Europe Dormant In trial In trial In trial Pending In trial

Reviewed in this article.

Hentschel, cited by Schmidt (1994), reviewed 39 published reports with open-label data. Clinical improvement occurred in 918 of 1,369 subjects and full seizure control in 14%. The largest trial was in Can- ada, where 1,300 people with refractory seizures were treated with clobazam (Canadian Clobazam Cooperative Group, 1991) in doses ranging from 2.5-150 &day (mean 30 mdday). Retrospective review of the population showed that 40% to 60% experienced at least a 50% seizure reduction with addition of clobazam. Schmidt (1994) recently reviewed eight placebo-controlled trials in patients with refractory partial and secondarily generalized tonic-clonic seizures, published from 1981 to 1989. The responder rate, defined as at least a 50% reduction in seizure frequency, exceeded 50% in the ma- jority of trials. Over the 1 to 4 months of the trials, a median of 16% to 21% of patients became seizure- free. CLB is effective in children. A double-blind crossover study in Canada of children with seizures showed a 52% responder rate (Keene et al., 1990).

Side effects occur in about 25% of patients receiving CLB (Remy, 1994), mainly sedation, ataxia, weakness, memory problems, and behavioral changes. A few patients have developed paranoid psychosis while receiving CLB (Scott and Moffett, 1988). Development of tolerance is the major prac- tical limit to CLB, appearing in one-third to one-half of patients who receive it continually for 1 to 6 months (Remy, 1994).

Few studies report on CLB in monotherapy, and none examine whether CLB is more effective than other BZDs. CLB is produced by Hoechst in Ger-

many and is available in at least 50 countries (Schmidt, 1994), but CLB is not under current clinical study in the United States.

DEZINAMIDE @ZN)

DZN, previously called ADD-94057 and AHR- 11748, is a metabolite of fluzinamide (FZN), a putative AED. Like FZN, DZN appears to bind to voltage-sensitive sodium channels and has an antiepileptic profile similar to that of PHT and CBZ. DZN has no obvious interaction with the y-aminobutyric acid (GABA) receptor complex. The Ep- ilepsy Branch of NINDS sponsored an open-label study of DZN, in which 40% of 16 patients entered showed at least 50% reduction of seizure frequency (F'rivatera et al., 1992). Side effects of DZN include blurred vision, diplopia, ataxia, lightheadedness, headache, confusion, and dizziness. One patient developed hypomania. DZN was manufactured by A. H. Robbins and was under development by Ath- ena Neurosciences in San Francisco, but development has now been deferred because of a change in priorities of the sponsor.

nUNARIZINE (FNR)

FNR, a product of Janssen Pharmaceuticals, and a related drug, cinnarizine, are class IV calcium- channel antagonists (Todd and Benfield, 1989). Nevertheless, these drugs may work via other mechanisms, as FNR interacts with voltage- dependent sodium channels (Pauwels et al., 1991). FNR has been available for many years in Europe and elsewhere as an antihistamine, cerebral vasodi- lator, and headache remedy. The serum half-life of flunarizine is very long, ranging from 2 to 7 weeks, and fixed dosages result in variable individual serum levels (Pledger and Treiman, 1991). FNR causes no significant laboratory abnormalities nor alterations in levels of concurrent AEDs (Alving et al., 1989; P1 ger and Treiman, 1991). Studies of FNR 5-15 2 dday have yielded conflicting results, with some showing benefit (Overweg et al., 1984; Battaglia et al., 1991) and others showing little benefit (Alving et al., 1989; Keene et al., 1989; Nakane et al., 1989). About 20% to 66% of patients in the controlled trials experienced at least a 50% improvement in partial seizure frequency when FNR was added, but about 3% to 5% experienced increased seizures on FNR. Side effects consist of drowsiness, weight gain, and a s i a i c a n t incidence of extrapyramidal side effects (Todd and Benfeld, 1989). At present, an NINDS-sponsored multicenter trial of FNR is under way. The drug has

NEW ANTIEPILEPTIC DRUGS S107

“orphan;drug” status for therapy of alternating hemiplegia.

LORECLEZOLE (LCZ)

LCZ is a triazole derivative, unlike all other available AEDs (de Beukelaar and Tritsmans, 1991). In animal models LCZ has an antiepileptic profile similar to that of the barbiturates and BZDs (Pohl and Mares, 1990; Ashton et al., 1992). Pilot studies showed that six of nine patients could be switched to LCZ monotherapy with no major increase in seizures (Rentmeester and Hulsman, 1992). In a double-blind add-on trial in patients with uncontrolled partial seizures, 19% of those with LCZ experienced at least a 50% reduction in seizure frequency (Rentmeester et al., 1991~). Patients in this trial achieved plasma levels of 1-2 mg/L. When levels were pushed to 6 mg/L in an open-label extension, 39% of patients showed at least a halving of their seizures (Rentmeester et al., 1991b). Few adverse effects or laboratory abnormalities have thus far been detected. LCZ is presently in phase I1 clinical trials, sponsored by Janssen Pharmaceuticals.

MILACEMIDE (MLM)

MLM, 2-N-pentylaminoacetamide, is a glycine agonist. Glycine is an important inhibitory neuro- transmitter in brainstem and spinal cord. MLM was sponsored by Monsanto-Searle in clinical trials for epilepsy after initial suggestion of efficacy in open-label trials (Houtkooper et al., 1986). An unpublished, multicenter, double-blind, placebo- controlled trial in the United States showed unimpressive efficacy, and interest as an AED has declined. MLM has also been tried for other condi- tions, including Alzheimer’s disease (Dysken et al., 1992) and myoclonus (Brown et al., 1991), as glycine has a facilitory action on the NMDA site of the glutamate receptor. Results have not been impressive, however, and MLM is presently dormant.

MK-801

The Merck drug MK-801 has generated excite- ment in research circles as an NMDA-associated channel blocking agent (Wong et al., 1986). It is known from research studies that the NMDA subtype of the glutamate receptor is involved in patho- genesis of certain seizure disorders (Dingledine, 1983). The NMDA-associated channel-blocking action of MK-801 is similar to that of dissociative an- esthetics, including ketamine and phencyclidine. In high dosage, MK-801, like these other agents, has psychotomimetic side effects, severely limiting use

in treatment of epilepsy. In lower dosage, clinical trials in the United Kingdom and in the United States have found only limited efficacy against seizures (Troupin et al., 1986). MK-801 is now being studied primarily as a stroke-protective drug.

NAFIMIDONE

Nafimidone is produced by Syntex Research Laboratories, and studies have been supported by the Epilepsy Branch of NINDS. The drug is an im- idazole derivative with a profile of action in animal epilepsy models similar to that of PHT and CBZ. Pilot studies showed a 33-98% improvement in seizure control in 12 patients treated with 600 mg/day of nafhidone for up to 1 year (Treiman et al., 1985). Subsequent unpublished work has found that nafimidone has a relatively poor therapeutic/toxic ratio, and is not presently under active development.

ORG-6370

The putative AED ORG-6370 (Kapetanovic et al., 19861, developed by Organon Scientific Group in The Netherlands, is active against maximal elec- troshock (MES) seizures in rodents, and has a high therapeutic/toxic ratio in animals. A small number of open studies in Europe and in the United States have suggested some efficacy in a variety of differ- ent seizures, but anticholinergic side effects have been a problem. There have been recent concerns that ORG-6370 may increase seizures in individuals with photosensitive epilepsy. Development of ORG-6370 is now on hold.

OXCARBAZEPINE (OCBZ)

OCBZ (Trileptal; 1O,ll-dihydro-lO-oxo-5H-di- benz(b,f)azepine-5-carboxamide) is a Ciba product developed as a 10-keto analogue of CBZ (Jensen et al., 1991) (Fig. 1).

OCBZ and CBZ appear to have a similar profile and degree of efficacy against partial and generalized tonic-clonic seizures (Reinikainen et al., 1987; Dam et al., 1989; Friis et al., 1993; Kubova and

~ \ N H

FIG. 1. Structure of oxcarbazepine.

Epikpsia, Vd. 36. Suppl. 2, 1995

s108 R . FISHER AND D. BLUM

Mar&, 1993). Dosage is about 50% higher for OCBZ to achieve similar potency. OCBZ has a serum half-life of 1.&2.5 h (Dickinson et al., 1989), but is metabolized to the 10-hydroxy active metabolite, which has an 8-h half-life (Hooper et al., 1987). OCBZ and its 10-hydroxy metabolite are each 4040% bound to plasma proteins (Patsalos et al., 1990). Serum levels in the Scandinavian Multi- center Study were 57 f 20.2 pMIL on average, but levels correlated poorly with drug‘toxicity (Dam et al., 1989). OCBZ induces hepatic microsomal enzymes in rats (Wagner and Schmid, 1987) but not in humans (Larkin et al., 1991).

In preliminary studies, side effects appear to be somewhat less than those of CBZ, particularly with respect to depression of white blood counts and incidence of rashes (Friis et al., 1993; Oller et al., 1993). OCBZ serum levels, unlike CBZ levels, are not affected by dextropropoxyphene (Morgensen et al., 1992), erythromycin (Keranen et al., 1992a), or cimetidine (Keranen et al., 1992b). Fatigue, ataxia, and headaches do occur in a dosage-related fashion with OCBZ. Cognitive side effects in patients receiving chronic OCBZ are similar to those with chronic PHT (Aikia et al., 1992), but OCBZ is less sedative than CBZ (Dickinson et al., 1988). One double-blind crossover study of OCBZ 600 mglday observed increased alertness compared to the group receiving placebo (Curran and Java, 1993). In some, therefore, OCBZ may have a stimulant effect, al- though further trials will be required to confirm this finding. Unlike CBZ, OCBZ does not slow peripheral motor nerve conduction manner et al., 1988). In one investigation, only about one-quarter of patients allergic to carbamazepine were allergic to OCBZ (Pirmohamed et al., 1991), but three of three showed crossreactivity in another study (Beran, 1993). Hyponatremia can occur with both drugs. Patients with OCBZ dosages above 30 mgkglday are at particular risk for hyponatremia (Johannes- sen and Nielsen, 1987), including hypoglycemic coma (Nielsen et al., 1988; Steinhoff et al., 1992).

A retrospective study (Friis et al., 1993) of OCBZ was performed at eight centers from 1981 to 1990. Mean dosage was 18 mglkglday in adults and 30 mg/kg/day in children, divided b.i.d. or t.i.d. Mean plasma level of the hydroxy metabolite was about 70-80 pM. Seizure frequency was not compared to placebo, but most patients did at least as well as with CBZ. One-third had adverse events (dizziness, sedation, fatigue, and rash, each at an incidence of 6%). Of patients with available data, 25% experienced hyponatremia. Patients who were suffering CBZ side effects experienced remission of these side effects in 88% of cases, with no loss of seizure

control (Pendlebury et al., 1989). OCBZ is now in phase I1 clinical trials in the United States. A pilot study with 10 patients undergoing presurgical evd- uation showed good preliminary safety and efficacy (Fisher et al., 1994). The European experience has been reviewed (Andermann, 1994).

PROGABIDE (PGB)

PGB, as its name suggests, was synthesized by Synthelo Laboratory in France to be a “pro” drug for GABA. In animal studies, PGB has a wide spectrum of anticonvulsant actions, but little evidence exists for a mechanistic relationship to GABA systems. PGB raises PHT concentrations and shifts metabolism of CBZ to the epoxide form (Brundage et al., 1987). The usual dosage range in clinical trials has been about 15-60 mg/kg/day (Schmidt and Utech, 1986). Several open-label uncontrolled studies suggested efficacy and safety of PGB in a variety of seizure types (Martinez-Lage et al., 1984; Bena- ssi et al., 1988), but other studies in partial (Dam et al., 1983) and absence (Stefan et al., 1988) seizures failed to show benefit. Two controlled studies of PGB as an add-on demonstrated unimpressive efficacy (Schmidt and Utech, 1986; Leppik et al., 1987). A trial of PGB versus valproate (VPA) and placebo in 64 patients with intractable partial and secondarily generalized seizures was not completed because PGB caused significant elevations of liver enzymes and was less efficacious than VPA (Craw- ford and Chadwick, 1986). Signifcant liver toxicity is possible with the use of progabide (Muiioz et al., 1988), and about 1045% of patients receiving PGB develop elevation of serum AST. PGB is available in France but not in the United States at present because of concern regarding efficacy and risks of hepatotoxicity.

RALITOLINE (RLT)

RLT is a thiazolidinone derivative under development by Warner-Lambert Parke-Davis (Anhut et al., 1991). The spectrum of anticonvulsant activity in animal model systems is similar to that of PHT and CBZ, and RLT is believed to act on the voltage- sensitive sodium channel (Rock et al., 1991). RLT has additional action against clonic seizures produced by PTZ. Ralitoline is extremely potent against MES and appears to have a very good therapeutic/toxic index in animal studies (Fischer et al., 1992). A disadvantage of RLT is a short half-life (Loscher et al., 1991). Little information is available from human trials, and development of RLT is presently dormant.

Epilepsia. Vd. 36, Suppl. 2, 1995

NEW ANTIEPILEPTIC DRUGS s109

STIRIPENTOL (STP) STP [4,4 dimethyl- 1-(3,4-methylenedioxy-

pheny1)- 1-penten-3-01] is a novel compound derived from alcohol, effective against MES in animals (Vincent, 1991). Pharmacokinetics of STP were reported by Levy et al. (1984). Doseserum level re- lations are highly nonlinear. Stiripentol is an inhibitor of rat cytochrome P450 enzymes (Mesnil et al., 1988), in distinction to most AEDs (except VPA), which induce the system. STP inhibits clearance of CBZ (raises serum levels by about 50%), and re- duces transformation to the CBZE (Kerr et al., 1991). PHT and phenobarbital (PB) levels also are increased by 25-50% (Loiseau et al., 1988). Be- cause STP blocks conversion of CBZ to CBZE and has the opposite effect from CBZ on the hepatic microsomes, the two drugs might form a rational combination therapy. This hypothesis was supported in a monkey model of partial seizures (Lock- ard and Levy, 1988).

A few open-label studies in Europe have suggested that STP is effective against partial seizures (Rascol et al., 1989). In one small open-label pilot study, 66% of 11 patients (mostly symptomatic partial epilepsies) administered STP had at least a 50% improvement in seizures (Loiseau et al., 1988). Equally impressive were preliminary results against absence seizures. STP, administered to 10 children ages 6 to 16 years in doses of 1-3 glday, generating levels of 4-22 mg/L, decreased atypical absence seizures by a mean of 70% (Farwell et al., 1993). Side effects were mainly gastrointestinal upset and leth- argy. Further development is being managed by Biocodex Laboratory, and additional clinical trials are in preparation.

TIAGABINE (TGB)

TGB, a derivative of nipecotic acid [r( - )n-(4,4- di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid hydrochloride, formerly NO-3281, is an Abbott Pharmaceutical- and Novo Nordisk-sponsored AED, designed to serve as a GABA uptake inhibitor (Pierce et al., 1991; Andersen et al., 1993) (Fig. 2).

In rats, TGB increases brain levels of GABA (Fink-Jensen et al., 1992). TGB is a more specific blocker of GABA uptake than is nipecotic acid, because the latter, but not the former, also serves as a substrate for the GABA-uptake carrier and as a false transmitter (Roepstorff and Lambert, 1992). TGB sigdkantly prolongs the duration of inhibitory synaptic potentials (Thompson and Gahwiler, 1992). TGB is effective in several animal models of the epilepsies, but only at very high doses in MES

1

'

S COOH

HCI

FIG. 2. Structure of tiagabine.

seizures (Nielsen et al., 1991). Therapeutic/toxic ra- tios in animal models are very favorable. In animals, TGB promotes little development of tolerance and no teratogenicity. A microdialysis study in a patient undergoing presurgical evaluation for epilepsy surgery showed a 50% rise in hippocampal GABA concentration 90 min after a 16-mg single oral dose of TGB (During et al., 1992). Another patient with an atrophic hippocampus exhibited no rise.

Open trial experience to date suggests that TGB is efficacious in some patients with intractable seizures (Mengel et al., 1990, 1991; Chadwick et al., 1991; Richens et al., 1992). TGB has a half-life of approximately 7 h. Typical dosages in clinical studies have ranged from 8 to 56 mg/day divided into four doses. Abbott Laboratories and Novo Nordisk presently are sponsoring several ongoing multicenter, double-blind, placebo-controlled trials of TGB (Mengel, 1994). The largest controlled trial has thus far been the M91-603 study by the Tiagabine Study Group (Rowan et al., 1993). Preliminary observations from 322 patients from 21 sites were reported. All patients had more than eight refractory complex partial seizures in a 12-week baseline period. Age range was 12 to 75 years. Subjects re- ceived one to three baseline AEDs (not VPA), which were continued through the trial. Patients re- ceived placebo (n = 90), or TGB 16 mg/day (n = 61), 32 mg/day (n = 86), or 56 mg/day (n = 55) after a 4-week dose titration period. Of the 297 patients randomized, 243 completed and 53 discontinued prematurely: 12 for lack of efficacy, 32 for toxicity, one for an intercurrent event, and eight for admin- istrative reasons. There was a dose-dependent increase in patients experiencing at least a 50% reduction in seizures. Overall, 25% of patients receiving TGB 56 mg/day responded with a halving of their seizure frequency, but only 3% became seizure-free. Adverse events occurring at rates greater than placebo included ataxia, dizziness, nervous- ness, abnormal thinking, and tremor.

Epilepsia. Vd. 36. Suppl. 2 , 1995

Sl lO R . FISHER AND D. BLUM

TOPIRAMATE (TPM)

TPM [2,3:4,5-bis-O-(l-rnethylethylidene)-~-~- fructopyranose sulfamate; McN-4853, TPMI is under development by the RW Johnson Pharmaceuti- cal Research Institute and McNeil Pharmaceuticals as an AED (Fig. 3).

The antiepileptic profile of TPM is similar to that of PHT and CBZ, with action against partial and generalized seizures and against amygdala-kindled seizures in the cat (Nakamura et al., 1993). TPM is a weak carbonic anhydrase inhibitor (Shank et al., 1991) and also blocks rapid neuron firing, consistent with block of voltage-dependent sodium and calcium channels (Coulter et al., 1993). TPM may also act on the AMPA (quisqualate) subtype of the glutamate receptor.

Clinical trials of TPM employed total daily doses in the range of 200 to 1 ,ooO mg. The half-life of TPM is 18-24 h, protein binding is less than 14%, and clearance is hepatic and renal. TPM increases CBZ levels by about 20%. Conversely, PHT decreases TPM levels. TPM is teratogenic in animal models.

Definitive clinical studies have not been published, except in abstract form, at the time of this writing. As part of a larger multicenter study, 13 patients were randomized to TPM 800 mg/day, or placebo, for a titration interval of 6 weeks and to a fixed-dosage regimen for 8 more weeks. Of the 5 patients receiving TPM who completed the study, two had no response and three had a mean reduction of seizures of 77% (Ostergaard et al., 1992). Ben-Menachem et al. (1993) reported an add-on, double-blind, parallel, multigroup study of 200-800 mg/day TPM with 56 patients with intractable partial seizures. Half of the patients receiving TPM experienced at least 50% improvement. Asthenia (in 79%), weight loss, and cognitive dysfunction (in 32%) were the main side effects. In the United States, a double-blind, parallel, placebo-controlled study of TPM 100,200, and 300 mg b i d . was con- ducted in 17 patients with refractory partial seizures (Aranguiz et al., 1991). Of the 17 patients, 35% achieved at least a 50% seizure reduction. Placebo- controlled add-on studies “YD” and “YE,” total- ing 356 patients, were reported by Fincham et al. (1W). A dose-dependent increase of efficacy occurred up to 600 mg, with little improvement at 800 and 1,ooO mg per day. At 600 mg, 58% of patients experienced at least a 50% improvement in seizures. Adverse experiences consisted of cognitive dysfunction, dizziness, tremor, and headache, and were reversible with discontinuation of study medication.

Cognitive side effects of TPM can be limiting, In

‘ 0 FIG. 3. Structure of topiramate.

one study 83% of 18 patients receiving TPM 400 @day complained of cognitive side effects (Rosen- feld et al., 1992). These were more severe if dosages were rapidly increased. A long-term, open-label study in Norway (Engelskjgn et al., 1993) listed cognitive side effects, weight loss, and urolithiasis as reasons for discontinuing TPM. Over a dozen studies are in progress.

ZONISAMJDE (ZNS) ZNS (1,2-benzisoxazole-3-methanesulfonamide)

is a sulfonamide derivative with a profile of anticonvulsant efficacy similar to that of PHT (Fig. 4).

ZNS blocks T-type calcium currents, which may have a role in seizure spread (Suzuki et al., 1992). The bioavailability of ZNS is excellent (Seino et al., 1991). The plasma concentration is linear over the dose range of 0 to 800 mg. Volume of distribution is 1.77 Lkg, indicating distribution outside the plasma compartment. Protein binding is 37%. A typical dose in clinical trials was 7 mg/kg/day (400-600 mg/ day in adults, starting at 1.5 mgkg) producing a steady-state serum concentration of 20 pg/ml (Lep- pik et al., 1993). Metabolism is renal, with a half-life of 2 to 3 days, but half-life is shortened in poly- pharmacy to 1 to 2 days. The loading dose is rec- ommended to be 100 mg for week 1, 200 mg for week 2, and 400 mg for weeks 3 to 4; it should thereafter be adjusted. Plasma levels should be kept less than 40 pg/ml because of risk for renal stones. Drug interactions are few, and other AEDs are not usually adjusted. Tablet size is 100 mg.

ZNS appears to have efficacy against partial sei-

FIG. 4. Structure of zonisamide.

Wepsio. Vd. 36, Suppl. 2, 1995

NEW ANTIEPILEPTIC DRUGS S l l l

zures and in secondarily generalized seizures. An open-label, add-on study in 167 patients with intractable partial seizures showed a median reduction of baseline seizure frequency of 52% (Leppik et al., 1993). A European double-blind, add-on trial docu- mented 28% fewer seizures than in the placebo group (Schmidt et al., 1993). In the treatment group, 30% responded with 50% or better improvement and 6% became seizure-free. One open-label study of ZNS in 44 children ages 8 months to 15 years, at doses up to 12 mg/kg/day, showed efficacy in idio- pathic generalized epilepsy (Kumagai et al., 1991). A small number of patients with generalized seizures associated with Lennox-Gastaut (Peters and Sorkin, 1993) and with progressive myoclonus epilepsy (Henry et al., 1988) have benefited from addition of ZNS, but the tole of ZNS in treatment of primarily generalized epilepsies will require more study.

Adverse effects of ZNS include a fairly high incidence of drowsiness, multiple interactions with other AEDs, and cognitive impairment (Berent et al., 1987). There is a rarer incidence of rash, tremor, allergic reaction, decreased blood count, and elevation of hepatic enzyme levels. Approximately 2% of 700 patients in Europe and the United States receiving ZNS developed renal stones (Peters and Sorkin, 1993). The relatively high incidence of renal calculi terminated the United States ZNS trials. Studies continued in Japan, where renal stones rarely were observed. Development has thus progressed, and ZNS is in trial once again in the United States.

CONCLUSION

This is a time of substantial progress in development of AEDs. Over 22 new AEDs have been tested in people with epilepsy. FBM and GBP have been approved for marketing in the United States and LTG is expected soon. An additional dozen AEDs are in promising clinical trials or awaiting marketing approval in the United States. Among the more important new GABA-related AEDs are CLB, a GABA-benzodiazepine receptor agonist; TGB, a GABA uptake inhibitor; and VGB, a GABA metabolism inhibitor. OCBZ is a keto analogue of CBZ, with promise as an AED of at least equal efficacy and a lower side-effect profile. Novel compounds include TPM, ZNS, LCZ, RLT, and STP. Considerable experience has been obtained with TPM, which appears to be a potent and effective agent, but with a high incidence of cognitive side effects. ZNS is effective, but development was im- paired by induction of renal stones. No single AED overshadows the others, and the ultimate role of

each for mild or severe seizures of various types remains to be determined.

Acknowledgmenk A preprint of some of this material was included in a 1993 newsletter written by the senior author and distributed by the American Epilepsy Society (excerpts reprinted with permission).

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