Antiepileptic Drugs, 5th Edition

Drugs in Development

98

Drugs in Early Clinical Development

Emilio Perucca MD, PhD, FRCP (Edin)^*

Harvey J. Kupferberg MD^**

* Professor of Medical Pharmacology, Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia; and Consultant Clinical Pharmacologist, Institute of Neurology, C. Mondino Foundation, Pavia, Italy

** Epilepsy Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Although it is acknowledged that the second-generation antiepileptic drugs introduced in the 1990s represent a valuable addition to the therapeutic armamentarium, these drugs are far from ideal for a number of reasons. First of all, they fail to achieve the ultimate goal of producing complete seizure freedom in most patients with epilepsy refractory to older agents (33,83). Second, many of these drugs exhibit significant shortcomings in terms of adverse side effects, limited activity spectrum against different seizure types, and drug-drug interactions.

Development of newer drugs with an improved safety and efficacy profile depends to a large extent on expanding knowledge about the pathogenesis and neurobiology of epilepsy. In addition, basic science findings need to be translated into applied research because understanding the neurobiology of seizures does not necessarily mean that an effective therapy can be developed immediately through rational drug design. An example of this problem can be demonstrated by progress in knowledge about glutamate's action in the central nervous system (CNS). Although a large amount of basic research has been generated describing the glutamate receptor, its subtypes, and the channels that are influenced by it, none of the strategies aimed at counteracting specifically glutamatergic responses in the brain has as yet yielded a clinically effective treatment (84).

The persistence of major clinical needs provides a powerful driving force for continuous investment toward discovery of better antiepileptic drugs and, as a result of this, during the last few years a number of new chemical entities have been identified and tested in preclinical and clinical models. The compounds described in this chapter are among the latest to enter clinical development. Although history has demonstrated that only 1 of 10 compounds initially submitted for human testing will find its way to approval for clinical use, it is hoped that many of these agents will in fact fulfill their promises and eventually be of help to the multitude of patients whose seizures are not controlled by currently available anticonvulsants.

ANTIEPILEPSIRINE

Antiepilepsirine (3,4-methylendioxycynnamoylpiperine) is a potential antiepileptic drug that originally was extracted from a Chinese folk remedy, and subsequently chemically characterized and synthesized at Beijing Medical University. In preclinical studies, antiepilepsirine has been found to be effective against pentylenetetrazole (PTZ)-induced seizures at dosages of 150 to 500 mg/kg in rats (123, 124, 125). The compound also is active against audiogenic seizures in genetically epilepsy-prone rats, with a median effective dose (ED₅₀) of approximately 65 mg/kg (22,127). It is, however, ineffective in protecting against amygdaloid-kindled seizures (123). Neurochemical studies suggest that its anticonvulsant activity may be related to an increase in extracellular serotonin concentration (22,127).

A double-blind, add-on, crossover trial has been conducted in children with refractory partial or generalized epilepsies who were given antiepilepsirine (10 mg/kg/day) or placebo each for 3-month periods (125). Only 34 patients completed the study because the parents of 24 children refused permission to cross over to the alternate treatment at the completion of the first 3 months. In those patients who completed the 6-month study, seizures were fewer during the antiepilepsirine period than during the placebo period. There were no changes in serum levels of concomitant antiepileptic drugs, and no serious acute side effects were recorded.

P.914

AWD 131-138

AWD 131-138 [1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one] was selected for development by Asta Medica (Radebeul, Germany) because of its broad-spectrum anticonvulsant effects and its potency in tests predictive of anxiolytic activity. It is currently in phase I clinical development.

Anticonvulsant Activity in Animal Models.

In rats and mice, AWD 131-138 protects against seizures induced by maximal electroshock (MES) and supramaximal stimulation with PTZ and bicuculline (9,91,113). It also is effective in seizure threshold tests with intravenous (i.v.) PTZ and electrical stimulation in mice. Audiogenic seizures in DBA/2 and Frings mice are potently inhibited, with intraperitoneal (i.p.) ED₅₀ values of 2.6 and 5.0 mg/kg, respectively (9,114). AWD 131-138 increases dose dependently the threshold for induction of afterdischarges in amygdala-kindled rats, the effect being already detectable at 1 mg/kg i.p., the lowest dose tested. Secondary generalization of the kindled seizures is completely inhibited at 20 mg/kg i.p., and at doses of 20 and 30 mg/kg i.p., kindling acquisition also is significantly delayed. In WAG rats, a model for absence epilepsy, AWD 131-138 suppresses dose dependently spontaneous spike-wave discharges, with almost complete suppression at 30 mg/kg orally (p.o.) (114).

Activities in Other Models.

AWD 131-138 is active in several mouse and rat models of anxiolytic activity (92). In rats, the ratio between the median toxic dose (TD₅₀) in the Rotorod test and the dose inducing anticonvulsant and anxiolytic activity (~3 mg/kg) is 333 after p.o. administration

Mechanism of Action.

The mechanism of action of AWD 131-138 appears to involve, at least in part, dose-dependent blockade of voltage-activated calcium channels (9). An inhibiting action on the increase in action potentials firing induced by corticotropin-releasing factor in locus ceruleus neurons of murine brainstem slices also may be relevant for anxiolytic activity. AWD 131-138 shows very low affinity [median inhibitory concentration (IC₅₀) ~5.8 µmol/L] and very low intrinsic activity at benzodiazepine receptor sites (91,97), and it is not identified as a benzodiazepine-like drug in discrimination tests in primates (128).

GANAXOLONE

Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one, CCD 1042) is a member of a new class of neuroactive steroids called epalons, which allosterically modulate the type A γ-aminobutyric acid (GABA_A) receptor. The synthesis and development of this compound at CoCensys, Inc. (Irvine, CA) was stimulated by the observation that endogenously occurring metabolites of progesterone and deoxycorticosterone exhibit significant anticonvulsant activity in animal models (18). Ganaxolone has already undergone early phase II trials in patients with epilepsy.

Anticonvulsant Activity in Animal Models.

In rodents, ganaxolone shows potent protective activity against seizures induced by PTZ, bicuculline, aminophylline, t-butyl-bicyclo-phosphorothionate, fluorothyl, and corneal kindling, whereas its activity in the MES test is comparatively weak (5,15,32,65).

Mechanism of Action.

The anticonvulsant effects of ganaxolone are considered to be mediated by stereoselective, high-affinity positive modulation of the GABA_A receptor through an interaction with a specific recognition site (34). Although ganaxolone retains some structural similarity with progesterone, it has no detectable hormonal activity (6).

Pharmacokinetics.

After oral administration with a high-fat meal in healthy volunteers, peak plasma ganaxolone concentrations are achieved within 1 to 3 hours and decline thereafter biexponentially, with a terminal half-life of 37 to 70 hours (75).

Drug Interactions.

In preliminary studies, add-on use of ganaxolone in patients with epilepsy did not result in changes in the plasma concentration of concomitant anticonvulsants (59).

Clinical Trial Data.

Tolerability studies in healthy volunteers used dosages up to 1,500 mg/day in three divided daily administrations for treatment periods up to 3 weeks. The most commonly observed adverse events were sedation, dizziness, headache, gastrointestinal disturbances, fatigue, unsteady gait, and impaired concentration (74,75). Side effects were more common in women than in men, despite similar plasma ganaxolone concentrations in both sexes. In a small trial in children given dosages up to 12 mg/kg three times daily, adverse events included somnolence, sleep disturbances, nervousness, constipation and, in one case, disturbed behavior and cognition (59). In another open-label, add-on trial in 20 children with refractory infantile spasms, ganaxolone given at dosages up to 36 mg/kg/day was well tolerated, and a 50% or greater improvement in seizure frequency was observed in one-third of the patients (47).

A proof-of-concept, double-blind, monotherapy study has been completed in which 52 patients undergoing assessment for epilepsy surgery were withdrawn from preexisting medication and randomized to receive ganaxolone (500 mg three times daily on day 1 and 625 mg three times daily on days 2 to 8) or placebo (55). Patients were required to exit the study if seizure control was deemed unacceptable. Fifty percent of patients randomized to ganaxolone completed the treatment period, compared with 25% of those randomized

P.915

to placebo. Although intent-to-treat analysis just failed to reach statistical significance, secondary analyses did suggest that ganaxolone had antiepileptic activity in these patients. In this study, the tolerability of ganaxolone was similar to that observed with placebo.

HARKOSERIDE

Harkoseride (R-2-acetamido-N-benzyl-3-methoxypropionamide) belongs to a series of propionamides synthesized at Schwarz Pharma in Manheim, Germany. These compounds have substitutions that generate an asymmetric carbon atom, giving rise to R- and S-enantiomers. Stereoselectivity for anticonvulsant activity resides only in the R configuration. Harkoseride can be termed a functional amino acid because it is an optical antipode of the naturally occurring amino acid L-serine. Its amphiphilic character imparts water solubility and transmembrane passage.

Anticonvulsant Activity in Animal Models.

Harkoseride is active in primary screening tests for anticonvulsant activity in mice and rats using electrically induced seizures. After i.p. administration, ED₅₀ in the MES test is 4.5 mg/kg in mice and 3.9 mg/kg in rats (9). In the audiogenic seizure susceptible Frings mouse model, i.p. ED₅₀ is 0.63 mg/kg. The protective indices in these models are excellent, being 6, >500, and 46, respectively. Harkoseride does not attenuate the clonic seizures induced by subcutaneous (s.c.) administration of PTZ, bicuculline, or picrotoxin. Hippocampal-kindled seizures in rats were suppressed after i.p. administration of harkoseride. Both the behavioral expressions of seizures and seizure afterdischarge duration decreased in a dose-dependent manner, and the ED₅₀ for harkoseride's ability to block the generalized kindled seizures was 13.5 mg/kg. The focal seizures (e.g., twitching of the vibrissae and automatisms) were attenuated at the higher doses.

Harkoseride is effective in blocking repetitive seizures in various models of status epilepticus, including the status induced by stimulation of the perforant pathway, the cobalt-homocysteine thiolactone model, and the lithium-pilocarpine model (9). In the focal model of status epilepticus induced by cobalt-homocysteine thiolactone, harkoseride blocks the secondarily generalized seizures (ED₅₀, 45.4 mg/kg), but focal seizures are unaffected.

Mechanism of Action.

Receptor binding studies have revealed an interaction at the strychnine-insensitive glycine site of the N-methyl-D-aspartate (NMDA) receptor complex. At this site, harkoseride displaces the radioligand 5,7-dichlorokynurenic acid, with an IC₅₀ of 5.2 µmol/L. To test the hypothesis that harkoseride modulates the strychnine-insensitive glycine receptor, the glycine agonist D-serine was administered intracerebroventricularly. The dose-response curve for harkoseride anticonvulsant activity in the MES test was shifted to the right when D-serine was combined (ED₅₀ for harkoseride alone 1.0 mg/kg, versus 2.7 mg/kg when combined with D-serine).

In electrophysiologic experiments, harkoseride did not affect NMDA-evoked currents at nonsaturating or saturating glycine concentrations. At -90mV, harkoseride (100 µmol/L) had no effect at the voltage-sensitive sodium channel, whereas phenytoin (100 µmol/L) produced a marked inhibition.

Pharmacokinetics.

In early studies to determine safety, tolerability, and pharmacokinetics, harkoseride was given to healthy male volunteers as single i.v. doses up to 300 mg, single oral doses up to 600 mg, and multiple oral doses up to 200 mg twice daily for 7 days. Absorption from the gastrointestinal tract was rapid (9). The plasma half-life was approximately 12 hours and plasma protein binding was less than 1%. The areas under the curve (AUC) after a 100-mg dose administered p.o. and i.v. were nearly identical, indicating virtually complete oral bioavailability. Plasma concentrations and AUCs were proportional to the administered dose.

Tolerability Data in Humans.

The most frequently observed adverse events in tolerability studies were headache, dizziness, and light-headedness.

LOSIGAMONE

Losigamone, or threo (±)5(R,S),α(S,R)-5-[(2-chlorophenyl) hydroxy-methyl)]-4-methoxy(5H)-furanone, is a racemic mixture of two enantiomers synthesized at the Willmar Schwabe Company in Karlsruhe, Germany. The S(+)-enantiomer (AO-242) is more potent than the R(-)-enantiomer (AO-294) in most pharmacologic tests (130).

Anticonvulsant Activity in Animal Models.

In experiments conducted in rodents, losigamone inhibits in a dose-dependent manner the tonic hindleg extension produced by electroshock, PTZ, bicuculline, nicotine, and 4-aminopyridine (108). It also attenuates the clonic seizures induced by PTZ, bicuculline, and picrotoxin, whereas it has no effect on the hindleg extension caused by strychnine and picrotoxin or the clonic seizures induced by NMDA. Five- to 7-day administration of 7 mg/kg losigamone to rats produced no evidence of tolerance to anticonvulsant activity (108). Losigamone has been found to protect against audiogenic seizures in rats and gerbils, and against PTZ-induced kindling in mice (84).

Mechanism of Action.

Losigamone reduces the frequency of spontaneous and stimulus-induced epileptiform discharges in the presence of picrotoxin (48) or low Ca²⁺ or

P.916

low Mg²⁺ in rat hippocampal slices (49). Similar results were observed in experiments using high potassium, low magnesium, and low calcium concentrations in hippocampal slices, and in experiments with low magnesium concentrations in the CA1 and CA3 region of the hippocampus and in the entorhinal cortex (84). In the entorhinal cortex, losigamone reduces repetitive spike firing elicited by depolarizing current and depresses moderately stimulus-induced excitatory postsynaptic potentials, whereas monosynaptic fast and slow inhibitory postsynaptic potentials are unaffected (103). Losigamone also has been found to decrease 4-aminopyridine-induced epileptiform activity in rat hippocampal slices (129). A primarily presynaptic mode of action dependent on functional sodium channels was suggested by experiments in cultured rat hippocampal neurons (26). Postsynaptic mechanisms also have been suggested for losigamone. A direct binding of losigamone with the GABA, picrotoxin, or benzodiazepine receptors has not been demonstrated. Losigamone does enhance chloride uptake in mouse spinal cord neurons in the absence of GABA, and potentiates the effects of GABA (23). In separate studies, racemic losigamone suppressed depolarizations induced by NMDA, but not those induced by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) (106). In another study, S(+) losigamone 100 µmol/L and 200 µmol/L significantly reduced both potassium- and veratridine-elicited release of glutamate and aspartate from cortical slices, whereas R(-) losigamone had no effect on release of the amino acids at 400 µmol/L (42). The conclusions from the latter study were that the mechanism of anticonvulsant activity was partly due to effects on glutamate release.

Pharmacokinetics.

In healthy volunteers, losigamone pharmacokinetics are linear after single oral doses ranging from 100 to 700 mg, or multiple doses up to 600 mg three times daily for 28 days (10,108). Losigamone is absorbed rapidly from the gastrointestinal tract, with peak plasma concentrations usually observed after 2 to 3 hours. The compound is approximately 60% bound to plasma proteins (109), and its apparent volume of distribution is approximately 1.5 L/kg (108). Mean apparent oral clearance (Cl/F) after single doses in healthy volunteers is approximately 300 to 400 mL/min, whereas mean half-life and mean residence time are approximately 4 and 7 hours, respectively. Although these estimates are based on measurement of racemic drug concentrations, there are important pharmacokinetic differences between enantiomers. A single-step liquid-liquid extraction followed by a reverse-phase high-performance liquid chromatography on a chiral column was used to separate and quantitate the enantiomers of losigamone in human plasma after oral administration of racemic losigamone (115,116). The apparent oral clearance of the R(-)-enantiomer was found to be approximately 10-fold higher than that of the S(+)-enantiomer (84,115). In healthy volunteers, the half-life of the R(-)-enantiomer was approximately 2.2 hours, compared with 4.8 hours for the S(+)-enantiomer. Studies based on recording of auditory evoked potentials in healthy volunteers suggest that the duration of effect may be longer than anticipated from the plasma half-life (101).

Only traces of unchanged losigamone are detected in urine. Approximately 15% of an orally administered dose is excreted in urine as a glucuronide conjugate. A conjugate also accounts for 11% to 32% of the total concentration of the drug in plasma (118). Losigamone undergoes oxidative biotransformation. Of five metabolites identified from human liver microsomes, M1 and M5 were identified as phenolic analogues, with M5 probably corresponding to 5′-hydroxy-(±)-losigamone (115). Two additional metabolites, M3 and M4, were considered to be precursors of M5, whereas the fifth metabolite, M2, appeared to be a nonphenolic substance. Metabolism is stereoselective, with M1 being primarily produced from the S(+)-enantiomer and M3, M4, and M5 being formed preferentially from the R(-)-enantiomer. The main cytochrome P450 (CYP) isoenzyme involved in the metabolism of both enantiomers appeared to be CYP2A6. In vitro, the formation of the M1 metabolite was markedly inhibited by R(-)-losigamone.

Drug Interactions.

Losigamone elimination is accelerated by concomitant administration of enzyme-inducing anticonvulsants. Cl/F values slightly in excess of 500 to 600 mL/min and mean half-lives of approximately 3.8 hours have been described in patients comedicated with carbamazepine and phenytoin, resulting in plasma losigamone levels that are reduced by approximately one-third compared with those observed in non-comedicated healthy volunteers receiving comparable doses (24,51,53). Losigamone pharmacokinetics do not appear to be affected by valproic acid (52) and lamotrigine (24).

In clinical studies, losigamone did not affect the serum concentration of phenytoin, carbamazepine, carbamazepine-10,11-epoxide, and lamotrigine (52,99,108). Likewise, losigamone has not been found to affect the metabolism of antipyrine and caffeine (10). At a dosage of 1,000 mg/day, losigamone may reduce slightly the plasma concentration of valproic acid (52,53).

Clinical Trial Data.

Open pilot studies suggested that the optimal dosage of losigamone, added to preexisting anticonvulsant medication, may be in the order of 1,500 mg/day in three divided doses (84). In a randomized, double-blind, parallel-group, add-on trial completed in 203 patients with refractory partial epilepsy (27), median reduction in seizure frequency in the group allocated to losigamone (500 mg three times daily) was significantly greater than that in the placebo group, but the magnitude of the effect was relatively modest (15% versus 7%, p < .005).

P.917

 

Adverse events most commonly associated with losigamone include dizziness and fatigue. Headache, sedation, diplopia, ataxia, dysarthria, restlessness, nausea, vomiting, and palpitations have been reported with a lower frequency (10,84). Although an elevation of liver enzymes has been described, none of over 400 patients included in clinical trials at dosages up to 1,500 mg/day dropped out because of hepatic toxicity (10).

NPS 1776

Many carboxylic acids and their ester and amide derivatives are known to have CNS activity and to protect experimental animals against PTZ-induced seizures (54). NPS 1776 (3-methylbutanamide, or isovaleramide) is a branched-chain aliphatic amide originally discovered by NPS Pharmaceuticals, Inc. (Salt Lake City, UT) Exclusive worldwide rights to the development and marketing of this compound have been acquired by Abbott Laboratories (Abbott Park, IL).

Anticonvulsant Activity in Animal Models.

NPS 1776 possesses in animal models an activity profile comparable with that of valproic acid, with a range of findings predictive of broad-spectrum efficacy against partial and generalized seizures (126). The p.o. ED₅₀ against MES-induced tonic extension seizures is 76 mg/kg in rats and 913 mg/kg in mice. The ED₅₀ in blocking PTZ-induced clonic seizures after p.o. administration is 205 and 748 mg/kg in rats and mice, respectively (9). In the i.v. PTZ seizure threshold test, NPS 1776 elevates seizure threshold. NPS 1776 also is active in attenuating the tonic phase of sound-induced seizures in the Frings mouse, with an ED₅₀ of 207 mg/kg after p.o. administration. NPS 1776 also protects against clonic seizures induced by s.c. picrotoxin (ED₅₀, 103 mg/kg), and is partially effective against clonic seizures induced by s.c. bicuculline in mice. In experiments conducted in Frings mice, no evidence of tolerance to the anticonvulsant effect was observed when animals were treated daily with NPS 1776 for 4 consecutive weeks.

In animal models of partial seizures, NPS1776 blocks the fully generalized kindled seizures in corneal- and amygdala-kindled rats, with ED₅₀ values of 127 and 140 mg/kg, respectively (9). The effects of NPS 1776 are comparable with those of valproate on both behavioral effects and electrographic seizure duration. NPS1776 also has been found to delay the acquisition of kindling in the amygdala-kindled rat, suggesting that it may exhibit antiepileptogenic effects.

Mechanism of Action.

As is the case with valproic acid, the mechanism of the anticonvulsant action of NPS 1776 has not been clarified. NPS 1776 does not interact in any in vitro receptor assay at concentrations up to 300 µmol/L.

Pharmacokinetics.

When administered as an oral solution to healthy volunteers at doses ranging between 100 and 1,600 mg, NPS 1776 is absorbed rapidly from the gastrointestinal tract and peak plasma concentrations are achieved in 30 to 45 minutes (9). NPS 1776 does not bind to plasma proteins and shows a relatively short half-life of approximately 2.5 hours. Although half-life values were similar across the explored dose range, there was a trend for apparent oral clearance and volume of distribution to decrease slightly with increasing single oral doses. Renal excretion does not appear to play a major role in NPS 1776 elimination, with only 2% to 4% of the administered dose being excreted in urine within 24 hours.

After treatment with total daily doses of 1,200 to 2,400 mg, given in three divided administrations, pharmacokinetic parameters are essentially the same as those observed after a single dose. Because of the short half-life, steady-state plasma levels are achieved in 2 days. Intersubject variability in pharmacokinetic parameters appears to be relatively low, and peak plasma concentrations and AUC values are proportional to dose.

Drug Interactions.

NPS 1776 does not inhibit any of the major CYP drug-metabolizing enzymes in experiments performed in vitro.

Tolerability Data in Humans.

Dosages up to 2,400 mg/day in three divided daily administrations have been tolerated well in healthy volunteers (9).

NW-1015

NW-1015, formerly known as PNU-151774E, was originally discovered by the Pharmacia-Upjohn group (Milan, Italy) (85), and currently is being developed by the Newron company in Gerenzano, Italy. Chemically, it corresponds to (S)-(+)-2-4-[(3-fluorobenzyloxy) benzylamino] propanamide methansulfonate. Pharmacologically, it combines multiple mechanisms of action, including blockade of voltage-dependent sodium channels, modulation of calcium channels, and inhibition of monoamine oxidase B (MAO-B) activity.

Anticonvulsant Activity in Animal Models.

NW-1015 prevents seizure spread in a wide variety of animal models, with a potency similar to or greater than that of most classic antiepileptic drugs (28). The oral ED₅₀ in the MES test is 8.2 mg/kg in mice and 12.8 mg/kg in rats; these dosages are much lower than neurotoxic doses, the protective index (MES ED₅₀/Rotorod TD₅₀, p.o.) being 76 in rats (9). NW-1015 is effective against seizures induced by bicuculline, picrotoxin, 3-methyl-aspartate, strychnine, and NMDA, as well as against seizures induced by amygdaloid kindling in rats (9,28,71). In the kainate model in rats, NW-1015 protects against convulsions and the resulting neuronal damage,

P.918

with an approximately 40% reduction in number of animals experiencing status epilepticus observed at 10 mg/kg i.p. (70). In a model of partial complex seizures in the conscious monkey, NW-1015 25 mg/kg p.o. reduces the behavioral paroxysms associated with afterdischargegenerating stimuli to the amygdala; plasma levels associated with this effect are in the order of 5 µg/mL, and at plasma levels of 9 µg/mL, local afterdischarge also is significantly reduced (29).

Activity in Other Models.

A neuroprotectant activity of NW-1015 has been documented in its ability to prevent neuronal cell loss induced by kainic acid in rats and by cerebral ischemia in gerbils (84).

Mechanisms of Action.

NW-1015 binds to the batrachotoxin recognition site of the sodium channel with an IC₅₀ of 8.2 µmol/L, and it is more potent than carbamazepine, phenytoin, and lamotrigine as a blocker of voltage-dependent sodium channels (100). In rat hippocampal slices, NW-1015 inhibits the release of aspartate and glutamate evoked by veratridine and KCl stimulation. Additional properties include modulation of calcium channels (100), affinity for the sigma-1 receptor in receptor ligand assays (84), and selective inhibition of MAO-B (IC₅₀, 0.08 µmol/L) in rat and human brain tissue. It has been claimed that the latter effect, through reduction of free radical formation (111), might play a role in preventing epileptogenesis after trauma and cerebrovascular accident (9).

Pharmacokinetics.

NW-1015 shows linear pharmacokinetics. After single oral doses ranging from 1 to 10 mg/kg and multiple doses ranging from 1.25 to 5.0 mg/kg/day in healthy volunteers, peak plasma concentrations proportional to dose were reached in approximately 2 hours, and the elimination half-life was in the order of 21 to 23 hours (9). After multiple dosing, steady-state plasma levels were achieved at approximately day 5.

Drug Interactions.

In vitro, NW-1015 exerts no inducing or inhibiting activity on the main CYP isoenzymes known to be involved in the metabolism of other antiepileptic drugs (9).

Pharmacodynamic Studies in Humans.

In healthy volunteers, doses of NW-1015 as low as 75 and 150 µg/kg have been found to inhibit platelet MAO-B activity by up to 75%. Higher doses resulted in complete and long-lasting MAO-B inhibition, whereas MAO-A was unaffected even at the highest dose tested (10 mg/kg) (9).

In tolerability studies in healthy volunteers, NW-1015 was in general well tolerated. Headache, somnolence, and lightheadedness were transiently reported by a few subjects at the highest doses tested (10 mg/kg single dose and 5 mg/kg/day repeated dosing).

REMACEMIDE

The discovery of remacemide, or (±)2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide monohydrochloride, resulted from a screening program for new anticonvulsants and neuroprotectants conducted by Fisons (currently Astra-Zeneca Loughborough, England) (17). Remacemide has undergone extensive clinical studies, but development plans are being reassessed after the compound was found to be inferior to carbamazepine in a recent monotherapy trial (9).

Anticonvulsant Activity in Animal Models.

In mice, remacemide is active against seizures induced by MES (ED₅₀, 48 mg/kg p.o., versus 22 mg/kg p.o. in the rat), NMDA (ED₅₀, 57 mg/kg. i.p.), kainic acid (ED₅₀, 60 mg/kg), and 4-aminopyridine (ED₅₀, 18 mg/kg i.p.) (9,17,31,79,107). It also is effective in antagonizing audiogenic seizures in mice and status epilepticus induced by injection of homocysteine thiolactone in rats with a cortical cobalt focus (17,119), whereas it shows no protection against seizures induced by PTZ, bicuculline, picrotoxin, or strychnine (17). Remacemide is ineffective in preventing kindled seizures induced by subthreshold bicorneal stimulation in rats (31,80), but at doses of 50 to 240 mg/kg s.c. it protects against kindled seizures induced by hippocampal stimulation in the same species (17).

In most animal models, the desglycinyl metabolite is more potent than remacemide, but it also is more toxic (17,79). Some differences in activity have also been detected between the (S)- and (R)-enantiomers of both parent drug and metabolite, with the (S)-forms being slightly more potent both in terms of anticonvulsant effect and neurotoxicity (31,79). These differences, however, were considered insignificant in biologic terms.

Activities in Other Models.

Remacemide exerts protective activity against neuronal damage caused by hypoxia and ischemia in rodents, cats, and dogs (3,79,84). In addition, remacemide potentiates the antiparkinsonian activity of levodopa in animal models of Parkinson's disease (36), an observation that led to exploratory trials in parkinsonian patients (84).

Compared with more potent noncompetitive NMDA receptor antagonists, remacemide lacks abuse potential (40) and produces fewer adverse behavioral effects (84). In toxicology studies, large acute doses of remacemide (≥160 mg s.c.), similar to other NMDA antagonists, cause neuronal vacuolation in various brain regions. This effect is thought to be due to exposure to high concentrations of the desglycinyl metabolite and has not been considered relevant to human safety issues (17).

Mechanism of Action.

Remacemide and its desglycinyl metabolite are low-affinity, noncompetitive antagonists of NMDA receptors, with IC₅₀s for inhibition of MK801

P.919

binding in the order of 68 µmol/L and 0.48 µmol/L, respectively (81). In vivo, the difference in potency between remacemide and its metabolite in inhibiting NMDA-induced seizures and death are less marked than expected from in vitro studies, presumably because in vivo, the metabolite contributes to the effects of the parent drug (17). In addition to blocking NMDA receptors, remacemide and its desglycinyl metabolite exhibit a blocking action on voltage-dependent sodium channels, with the metabolite again more potent in this effect (84,121).

Pharmacokinetics.

At dosages in the clinically used range, remacemide exhibits linear pharmacokinetics. Remacemide is absorbed rapidly from the gastrointestinal tract and reaches peak plasma concentration in 1 hour, whereas the desglycinyl metabolite takes 2 to 3 hours to reach maximum concentration (9). Concomitant ingestion of food may delay the time to peak concentration without affecting the extent of absorption. A volume of distribution of 5 to 6 L/kg, calculated after i.v. dosing in healthy subjects, indicates extensive penetration into tissues (17). The extent of binding to plasma proteins is 75% for remacemide and approximately 90% for the desglycinyl metabolite. In non-comedicated subjects, the half-life of remacemide is 3 to 4 hours, whereas the half-life of the desglycinyl metabolite is approximately 12 to 15 hours (17,77,80). In subjects dosed with 300 mg twice daily, mean peak and trough levels of remacemide were 1,069 and 124 ng/mL, respectively, compared with 143 and 89 ng/mL, respectively, for the metabolite (17). Remacemide is virtually entirely metabolized. In addition to cleavage of the glycine group by aminopeptidases in hepatic and extrahepatic tissues, biotransformation routes include CYP-mediated oxidation and glucuronidation to a carbamoyl glucuronide (17).

Drug Interactions.

Enzyme-inducing anticonvulsants such as carbamazepine, phenytoin, and barbiturates increase the clearance of both remacemide and its desglycinyl metabolite. In enzyme-induced patients, the AUCs of remacemide and desglycinyl remacemide are reduced by 25% to 50% and 70%, respectively, compared with values recorded in healthy subjects (17,56,57,102). Valproate, on the other hand, has no major effects on remacemide pharmacokinetics (84).

Remacemide inhibits CYP3A4 and by this mechanism increases the plasma concentration of carbamazepine by approximately 30% (56,58,88). Some increase in plasma phenytoin levels has been observed in occasional patients, probably due to concomitant inhibition of CYP2C9 (17,88), whereas plasma valproic acid levels usually are unaffected.

Antiepileptic Efficacy and Adverse Effects.

An initial double-blind, add-on, crossover trial in 23 patients with refractory partial epilepsy showed a median 33% seizure reduction during 4 weeks of treatment with remacemide, 150 mg four times daily, compared with placebo, but interpretation of the findings was complicated by a concomitant increase in serum carbamazepine levels (19). Two subsequent parallel-group, placebo-controlled, dose-ranging studies in similar populations of patients evaluated total daily doses of 300, 600, or 1,200 mg/day in a four times daily regimen, and 300, 600, or 800 mg/day in a twice daily regimen. Each treatment lasted for 8 weeks, there were approximately 60 patients per treatment arm, and changes in plasma levels of concomitantly administered carbamazepine and phenytoin were minimized by adjusting dosage of comedication. In the four times daily study, the proportion of patients showing at least 50% seizure reduction compared with baseline was 23% at the highest dosage, compared with 7% on placebo (pairwise comparison p = .03) (7). The twice daily study also demonstrated a greater responder rate at the highest dose than on placebo (30 versus 15%, pairwise comparison p = .05) (41).

Two monotherapy studies have been completed. The first involved treatment at 600 mg/day for up to 10 days in 61 patients undergoing neurosurgical evaluation and showed a longer time to fourth seizure with remacemide (6.8 days) than with placebo (3.8 days; p = .045), as well as a halving of median seizure counts (6.2 versus 12.8, p = .033) (8). The second was a multicenter, double-blind, flexible-dose comparison of remacemide (approximately 600 mg/day) with carbamazepine in 570 patients with newly diagnosed epilepsy, using sequential analysis of time to seizure recurrence. Preliminary results of this trial indicate that the efficacy of remacemide is inferior to that of carbamazepine (9).

To date, more than 1,400 patients have been exposed to remacemide in doses up to 2,400 mg/day, which corresponds to a safety database of over 1,200 patient-years. Most commonly observed adverse experiences include dizziness, ataxia, somnolence, abdominal pain, dyspepsia, nausea, vomiting, fatigue, and diplopia. These usually are mild and transient, but they have been a cause of discontinuation in approximately 15% of patients.

RETIGABINE

Retigabine, or N-[2-amino-4-(4-fluorobenzyl-amino)-phenyl] carbamic acid ethyl ester, formerly know as D23129, is a flupirtine derivative endowed with broad-spectrum anticonvulsant activity and low neurotoxic potential in a wide variety of animal models. It is being developed by Wyeth-Ayerst (Philadelphia, PA) and is undergoing phase IIb clinical trials.

Anticonvulsant Activity in Animal Models.

Retigabine protects against seizures in the threshold and supramaximal electroshock test, and it also is effective in inhibiting seizures induced by PTZ, picrotoxin, penicillin,

P.920

kainate, and intracerebroventricular NMDA (43,89,90,94), as well as audiogenic seizures in GEPR-3 and GEPR-9 rats (21) and DBA/2 mice (89). Retigabine exhibits considerable potency in delaying epileptogenesis and in protecting against focal and generalized seizures in the amygdala-kindled model (43,112). At a dosage of 5 mg/kg i.p., retigabine blocks status epilepticus induced by systemic administration of homocysteine thiolactone in rats with actively epileptogenic cortical cobalt lesions (120).

The electrophysiologic effects of retigabine have been investigated in a number of models. In 4-aminopyridine-treated rat hippocampal slices, retigabine suppresses spontaneous bursts in CA1 and CA3 areas, and eliminates afterdischarge-like trains of population spikes induced by a single electrical stimulation pulse without interfering with the normal evoked potentials (129). In other brain slice models of drug-resistant epileptiform discharges, retigabine was the only compound to produce a concentration-dependent inhibition of paroxysmal activity (1,2). In human brain slices obtained from surgical specimens, retigabine suppressed the epileptiform discharges that appear at low magnesium concentrations, and abolished spontaneous field potentials at concentrations that were without effect on evoked field potentials (110). Suppression of epileptiform discharges in a low-calcium hippocampal slice model suggests an extrasynaptic site of action (25).

Activities in Other Models.

Retigabine improves learning and memory in rat models of cerebral ischemia and electroshock-induced amnesia (89,90). Retigabine also has been found to exert dose-dependent activity in two models of neuropathic pain, the formalin test and a spinal nerve injury test (93).

Mechanisms of Action.

Retigabine is considered to act, at least in part, through selective activation of neuronal potassium channels. Enhancement of potassium conductance by retigabine has been demonstrated in a hippocampal slice preparation (39), in cortical neurons, in neuron growth factor-differentiated PC12 cells, and in oocytes expressing the KCNQ2 and KCNQ3 potassium channels, but not in glial and undifferentiated PC12 cells (69,95,96). Studies designed to characterize the mode of interaction with potassium channels showed that retigabine behaves as an M-channel agonist, possibly through a preferential interaction with the KCNQ2 channel, without interacting with the cyclic adenosine monophosphate modulatory site (69,98,122). Alterations in potassium channels have been implicated among causes of epilepsy (104). In addition to its action on potassium channels, retigabine may enhance GABAergic transmission through stimulation of GABA synthesis and amplification of GABA-induced currents (43, 44, 45,89).

Pharmacokinetics.

Retigabine exhibits linear pharmacokinetics, at least within the range of 50 to 600 mg as single doses or 50 to 200 mg twice daily as multiple doses (9). After oral administration, absorption is rapid and peak plasma concentrations usually are achieved within 1 hour. Retigabine is eliminated predominantly by N-glucuronidation and acetylation.

The elimination half-life in healthy volunteers is 9 to 11 hours on average, and it is similar after single or multiple doses. After a single 200-mg dose, retigabine half-life has been found to be slightly longer in elderly men (12.2 ± 4.2 hours) than in young men (8.5 ± 2.2 hours) or elderly women (8.9 ± 1.4 hours). In the same study, however, peak concentrations were higher in elderly women than in elderly men (717 ± 409 versus 354 ± 119 ng/mL) (9).

Drug Interactions.

In a pharmacokinetic study in healthy subjects, treatment with retigabine, 300 mg twice daily had no effect on the pharmacokinetics of a single 200-mg oral dose of lamotrigine. Likewise, administration of lamotrigine, 25 mg/day, did not affect the pharmacokinetics of a single dose of retigabine (9).

Clinical Trial Data.

In a safety and tolerability add-on study, a total of 46 patients with refractory partial seizures were divided into three groups and received mean maintenance retigabine dosages of 360, 800, and 950 mg/day, given in two divided doses for approximately 3 months. The most commonly observed adverse events included ataxia, blurred vision, and vertigo, which were of mild to moderate intensity in most cases. There were no abnormalities in laboratory data, vital signs, and ECGs. Eighteen patients entered a longterm extension study, and 13 are still on treatment at dosages between 600 and 1,400 mg/day (9).

SORETOLIDE

Soretolide [2,6-dimethyl N-(5-methyl-3-isoxazolyl) benzamide, ADD169026, D-2916] is a benzamide derivative being developed for the treatment of partial seizures with or without secondary generalization. Its preclinical anticonvulsant profile was established in collaboration with Biocodex (Paris, France) and the Antiepileptic Drug Development (ADD) Program, Epilepsy Branch, National Institute of Neurological Disorders and Stroke. In general, benzamides have been used for several clinical applications, and agents as pharmacologically distinct as anticholinergics, anesthetics, and antiarrhythmics are known to possess a benzamide structure. None of the approved anticonvulsants, however, belongs to this chemical class.

Anticonvulsant Activity in Animal Models.

Soretolide is active in preventing the tonic phase after MES stimulation in rodents. In the MES test, the ED₅₀ is 19.2 mg/kg p.o. in rats and 61.8 mg/kg i.p. in mice. Soretolide is metabolized in several species to an active hydroxylated derivative, 2,6

P.921

dimethyl N-(5-hydroxymethy-3-isoxazolyl) benzamide (D-3187), which is twice as potent as the parent compound in animal models of anticonvulsant activity. In the MES, the ED₅₀ of D3187 in rats and mice is 10.1 and 33.8 mg/kg, respectively (35,60). Both soretolide and its metabolite are inactive in protecting against the clonic seizures induced by PTZ, bicuculline, and picrotoxin, and in blocking the generalized or focal seizures in the hippocampal-kindled rat model after i.p. administration.

Mechanism of Action.

In vitro experiments failed to detect any interactions with the glutamate receptors, GABA receptors, and sodium receptors or channels.

Pharmacokinetics.

In clinical pharmacology studies, soretolide was given to healthy volunteers in oral doses ranging from 50 to 3,000 mg. Absorption was relatively rapid, with peak plasma levels usually observed in approximately 90 minutes. The peak concentration of the hydroxylated active metabolite, D-3187, was reached in approximately 3 hours and was consistently greater than that of the parent drug. Of the different formulations tested, the tablet and the suspension forms were found to be superior to the originally used capsules, and to produce peak plasma concentrations and AUC values proportional to dose within the dose range 125 to 1,000 mg. Soretolide is approximately 75% bound to plasma proteins, and studies in experimental animals indicate that it distributes uniformly throughout body tissues. In healthy volunteers, the half-life of soretolide is 3 to 9 hour, whereas the half life of D-3187 is 5 to 14 hours (84). Soretolide is not excreted unchanged in urine to any significant extent. It undergoes extensive oxidative metabolism by hydroxylation of the 5-methyl group of the isoxazole moiety, through intervention of the microsomal enzymes CYP1A2 and CYP2C19 (38,61). D3187 is further metabolized to the carboxylic acid (D-3269).

Drug Interactions.

Interaction studies in vitro showed that both soretolide and D-3187 inhibit the enzyme isoform CYP2C19. Although this may suggest a potential for inhibiting the metabolism of phenytoin, the inhibition constant for this reaction leads to the prediction that soretolide should cause little or no changes in serum phenytoin concentration.

Tolerability Data in Humans.

Soretolide has been given to patients with uncontrolled epilepsy in a tolerability study at dosages of 500 to 3,000 mg/day for up to 17 days. Fatigue, drowsiness, and headache were the most common adverse events observed at the highest dosage.

SPD 421

SPD 421, also known as DP16 or DP-VPA, is an interesting valproate prodrug that is intended selectively to deliver the active principle directly to the site of epileptic activity. It was originally developed by D-Pharm in Israel, and later acquired by Shire Pharmaceuticals in Andover, United Kingdom.

Mechanism of Action and Anticonvulsant Activity in Animal Models.

Based on a drug delivery technology known as Regulated Activation of Prodrugs (D-RAP, D-Pharm, Rehovot, Israel), SPD 421 is a complex consisting of one molecule of valproic acid chemically linked to a phospholipid carrier. Although the complex per se is considered to be pharmacologically inert, cleavage and the consequent release of valproic acid occurs after exposure to phospholipase A2 (PIA2), an enzyme that is released preferentially at the site of paroxysmal neuronal activity. The concept behind SPD 421 development is that seizure activity should trigger the local release of valproic acid, which would then selectively suppress the epileptic discharges. Exposure to the active principles outside the site(s) of epileptic activity should be minimized, with consequent reduction of the potential for adverse effects.

In animals subjected to convulsant stimuli, a first seizure usually is required to activate phospholipase A2. Therefore, as expected from its mode of action, SPD 421 protects preferentially against occurrence of a second seizure, whereas activity against a first seizure is absent or greatly reduced. In the PTZ test in mice, the ED₅₀ of SPD 421 for protection against a second seizure is 12 mg/kg (expressed as valproic acid equivalents), with a protective index of 6, compared with an ED₅₀ of 150 mg/kg and a protective index of 1.8 for valproic acid itself (9). Similar results were found using the s.c. picrotoxin test in mice and rats.

Using the audiogenic seizures model in Frings mice, SPD 421 given i.p. 1 hour before stimulus application shows an ED₅₀ of 4.5 mg/kg (valproic acid equivalents), compared with 220 mg/kg for valproic acid. In the same model, the duration of activity of SPD 421 is much longer when animals are stimulated every 2 hours compared with animals exposed to a single stimulation (9). Again, this is considered to be related to the greater local release of the active principle after repeated stimulation. SPD 421 is ineffective in the genetic absence epilepsy in rats from Strasbourg (GAERS) model of absence seizures, possibly because the mechanisms triggering seizures in this model may not result in the activation of phospholipase A2.

Drug Interactions.

In animal experiments, enzyme induction by phenobarbital has no effect on plasma SPD 421 levels, probably because SPD 421 is minimally metabolized by CYP enzymes. SPD 421 itself does not cause induction of carbamazepine metabolism.

Tolerability Data in Humans.

In a double-blind, placebo-controlled tolerability study in a total of 56 healthy volunteers, SPD 421 (up to 5 g as single doses and up to 1.25 g/day

P.922

as multiple dose, was well tolerated in general. The only adverse event reported was transient epigastric pain, and no dropouts were reported in any of the dosage groups (9).

STIRIPENTOL

Stiripentol is 4,4-dimethyl-1-[(3,4 methylenedioxy)phenyl] -1-penten-3-ol, an allyl alcohol that occurs in two enantiomeric forms. Its anticonvulsant properties were discovered by the Biocodex Laboratories in Paris, France over 20 years ago, and the compound still is being used clinically on a named basis despite the fact that its development was hampered by interactions with concomitant antiepileptic drugs.

Anticonvulsant Activity in Animal Models.

Stiripentol exhibits broad-spectrum activity against seizures induced by MES, PTZ, and bicuculline (68,86), spike-and-wave discharges in a genetic model of petit mal epilepsy in Wistar rats (73), and interictal electroencephalogram spike discharges in an alumina gel rhesus monkey model of focal epilepsy (66).

Mechanisms of Action.

The mode of action is poorly understood, but it may involve inhibition of the synaptosomal uptake of glycine and GABA (68,86), enhanced β-hydroxybutyrate dehydrogenase activity, and inhibition of GABA-transaminase (84).

Pharmacokinetics.

After oral administration, peak plasma concentrations usually are achieved within 2 hours. Stiripentol is 99% bound to plasma proteins and is eliminated according to capacity-limited, Michaelis-Menten kinetics (62). In one study in patients receiving concomitant anticonvulsants, the steady-state stiripentol concentration increased by approximately 250% with a dose increase from 600 to 1,200 mg/day, and a further doubling of the dose to 2,400 mg/day caused an almost 400% rise in serum concentration (63). Identified metabolic pathways include glucuronide conjugation (20% to 30% of the dose), opening of the methylenedioxy ring (11% to 14%), and O-methylation of catechol metabolites at positions 3 and 4 (17% to 24%) (68,76).

Drug Interactions.

Enzyme-inducing anticonvulsants accelerate stiripentol metabolism. At a dosage of 1,200 mg/day, stiripentol clearance in enzyme-induced patients is on average threefold higher than in non-comedicated subjects (63).

Stiripentol is an inhibitor of oxidative drug metabolism, leading to increased serum concentrations of phenytoin (63,68), carbamazepine (46), phenobarbital (63,68), primidone (4), clobazam, norclobazam (16,82,87), and valproic acid (64). Most of these interactions are clinically relevant and may require reduction in dosage of associated drugs.

Antiepileptic Efficacy and Adverse Effects.

In open studies, stiripentol has been reported to improve the frequency of both partial and generalized seizures, including typical and atypical absences, at maintenance dosages in the range of 1,000 to 3,000 mg/day in adults and 20 to 100 mg/kg/day in children (30,68,82). In a recent, open-label, pediatric add-on trial in a total of 212 children, 49% of patients showed a 50% reduction in seizure frequency, the best results being observed in partial epilepsies (82). Particularly good responses also were obtained in combination with clobazam in patients with severe myoclonic epilepsy of infancy, a finding subsequently confirmed in a doubleblind, placebo-controlled trial in 40 children (16). Despite the fact that the appearance of adverse effects (or a predefined treatment protocol) often led to a reduction in the dosage of comedication in these studies, serum levels of concomitant anticonvulsants were almost invariably higher during stiripentol treatment than at baseline, and therefore it has been difficult to establish to what degree pharmacokinetic interactions contributed to clinical improvement. Chiron et al. (16) suggested that patients on stiripentol may tolerate higher concentrations of concomitant anticonvulsants, particularly clobazam and norclobazam, compared with patients not receiving stiripentol, leading to an improved therapeutic index of associated therapy. When attempts were made to discontinue comedication and stabilize patients on stiripentol monotherapy, most patients showed a deterioration in seizure control (68).

The most commonly reported adverse effects include gastrointestinal disturbances (nausea, vomiting, gastric/abdominal discomfort, anorexia), weight loss, neurobehavioral disorders, insomnia, and drowsiness (68,82). Leukopenia also has been reported. Many CNS adverse effects may be managed through reduction in the dosage of concomitant antiepileptic drugs.

TALAMPANEL

Talampanel (LY 300164, GYKI 53773) is the R(-)-enantiomer of 7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5H)-2,3-benzodiazepine. This compound, discovered by Eli Lilly Co. (Indianapolis, IN) and currently being developed by Ivax, Miami, Florida, acts as a stereoselective noncompetitive antagonist of the AMPA subtype of the glutamate receptor (11). Although it is structurally considered a benzodiazepine, its affinity for the benzodiazepine receptor and spectrum of anticonvulsant activity differ from those of 1,4-benzodiazepines such as diazepam. Because of their specific AMPA antagonist activity, 2,3-benzodiazepines have been considered as potential therapeutic agents in a variety of neurologic disorders, including amyotrophic lateral sclerosis (ALS) (117) and levodopa-induced dyskinesias in patients with Parkinson's disease (50).

P.923

 

Anticonvulsant Activity in Animal Models.

Talampanel is effective in protecting against electrically and chemically induced seizures in rodents. The threshold for electrically induced seizures is increased dose dependently at doses above 2 mg/kg (20). In mice, talampanel is effective in inhibiting seizure spread in the MES test (ED₅₀, 4.6 mg/kg) and in raising seizures threshold in the s.c. PTZ test (ED₅₀, 16.8 mg/kg). Talampanel suppresses chemically kindled seizures at a dose of 12.5 mg/kg and electrically kindled seizures in mice at a dose of 20 mg/kg. When administered i.p. at a dose of 5 mg/kg, talampanel significantly reduces the seizure and afterdischarge duration, but it has minor activity in suppressing both generalized and focal seizures in fully kindled rats (13). Talampanel also has been found to antagonize seizures in a dose-related manner in a mouse model of phenytoin-resistant status epilepticus (9).

At doses that by themselves are inactive against electrically induced seizures (0.75 to 2 mg/kg), talampanel potentiates the anticonvulsant activity of carbamazepine, valproic acid, and diazepam (13,14,20).

Activity in Other Models.

The neuroprotective efficacy of talampanel in vitro was investigated in an embryonic rat hippocampal culture model of non-NMDA receptor-mediated excitotoxicity using kainic acid as an agonist at the AMPA/kainate receptor (72). Using lactate dehydrogenase efflux as a biomarker for cellular toxicity, talampanel attenuated kainate effects in a dose-dependent manner, with an IC₅₀ of 4 µmol/L. The (S)-enantiomer was inactive in this model. In vivo, talampanel has been found to be effective in protecting against the excitation of spinal neurons induced by electrophoretic application of NMDA and AMPA in anesthetized rats (67,78). Talampanel also protects against damage induced by bilateral carotid occlusion in gerbils, inhibits flexor reflexes in cats, and protects mice from memory-impairing effects of cerebral ischemia (9). Talampanel decreases contusion volume in a rat fluid percussion model of head trauma when given 30 minutes after the trauma.

In nonhuman primates, talampanel has been found to exert a modest antiparkinsonian activity when given alone, to potentiate the antiparkinsonian effect of levodopa in 1-methyl-4-phenyl-1,2,3,b-tetra hydropyridine (MPTP)-lesioned animals, and to attenuate levodopa-induced dyskinesias. These effects are seen at doses as low as 1 mg/kg and increase in magnitude at the well-tolerated dose of 10 mg/kg (50).

Talampanel induces microsomal drug-metabolizing enzymes in rats and mice (9).

Mechanism of Action.

Talampanel is a noncompetitive antagonist at AMPA receptor sites. In binding assays, talampanel does not appear to interact (>100 mmol/L K_i) with α₁- and β-adrenergic receptors or with dopamine type 1 (D₁), D₂, histamine type 1, GABA, 5-hydroxytryptamine type 2, and muscarinic receptors (9).

Pharmacokinetics.

Talampanel is well absorbed from the gastrointestinal tract, with peak plasma concentrations being observed at approximately 2.5 hours after an oral dose (84). Plasma protein binding ranges from 67% to 88%. Nonlinear kinetics have been observed after single and multiple doses in healthy volunteers, and evidence has been provided that elimination occurs by a combination of a first-order and a capacity-limited process, with the latter becoming saturated at plasma levels of approximately 200 ng/mL. At dosages producing plasma levels higher than these (single doses above 50 mg and multiple doses above 20 mg three times daily), the half-life is approximately 7 to 8 hours and plasma concentrations are expected to increase linearly with increasing dosages.

Talampanel is eliminated primarily by biotransformation, and one of the metabolic pathways involves acetylation. The apparent oral clearance at steady state has been found to be approximately 50% lower in slow acetylators than in fast acetylators (84).

Drug Interactions.

Talampanel is an irreversible inhibitor of CYP3A4 and therefore it may increase the plasma concentration of CYP3A4 substrates such as carbamazepine (9). On the other hand, the plasma levels of the cholesterol-lowering drug lovastatin were unchanged after 10 days of treatment with talampanel, 60 mg three times daily.

There is evidence that talampanel metabolism is partly mediated through inducible pathways. In fact, microsomal enzyme inducers such as phenytoin and carbamazepine were found to increase the clearance of talampanel in a 1-week drug interaction study in patients with epilepsy (9). On the other hand, valproic acid decreases the clearance of talampanel.

Antiepileptic Efficacy and Adverse Effects.

In a randomized, double-blind, add-on, crossover trial in 49 patients with refractory partial seizures, talampanel treatment was associated with a median 21% reduction in seizure frequency compared with placebo treatment, and 80% of patients had fewer seizures on talampanel than on placebo (9). The protocol required that the plasma concentrations of concomitant anticonvulsants be maintained within 30% of baseline, which led to a reduction in carbamazepine dose in six patients The 16 patients who did not receive carbamazepine comedication showed a similar (21%) seizure reduction. Most patients were receiving concomitant enzyme inducers, and the median dose of talampanel in these patients was 52 mg three times daily (versus a maximum allowable dose in this group of 75 mg three times a day), resulting in a mean plasma level of 125 ng/mL. The most commonly encountered adverse events were dizziness and ataxia, which occurred in 52% and 26%, respectively, of talampanel-treated patients. Discontinuation rates were 13% during the talampanel period and 11% during the placebo period.

P.924

 

Trials in Other Indications.

Forty patients with ALS who had been symptomatic for 2 years or less were included in a randomized, parallel-group, placebo-controlled trial (9). Eighty-five percent of patients assigned to talampanel achieved the maximum dosage of 50 mg three times daily, with a mean plasma level of 400 ng/mL. Talampanel-treated patients showed a 15% decrease in rate of decline on the Tufts Quantified Neuromuscular Examination scale and showed less deterioration than placebo patients on the ALS functional rating scale, although differences were not statistically significant. Dizziness and somnolence were the two most commonly observed adverse events in this study.

VALROCEMIDE

Valrocemide (N-valproyl glycinamide, TV 1901) is a N-acetyl derivative of valproic acid, selected for clinical development by Teva Pharmaceuticals (Petach Tikva, Israel) among a series of valproyl derivatives of GABA and glycine (12).

Anticonvulsant Activity in Animal Models.

Valrocemide shows broad-spectrum protective activity against electrically and chemically induced seizures (7,9,37,105). The ED₅₀ in the MES test is 73 mg/kg p.o. in rats and 152 mg/kg i.p. in mice. Valrocemide also raises seizure threshold, with an ED₅₀ of 127 mg/kg i.p. in the s.c. PTZ test in mice. The neurotoxic oral TD₅₀, determined by the gait and stance test in rats, is greater than 1,000 mg/kg, whereas the i.p. TD₅₀, determined by the Rotorod test, is 332 mg/kg in mice. In two separate types of kindling models, corneal and hippocampal kindling, valrocemide was capable of suppressing both generalized and focal seizures at doses below the TD₅₀. Valrocemide is effective in antagonizing seizure activity in two genetic models of epilepsy, the audiogenic seizure-prone Frings mouse and the lethargic mouse.

Mechanism of Action.

In animal models, the activity profile of valrocemide resembles that of valproic acid. Its precise mechanism of action remains to be defined.

Pharmacokinetics.

After administration of single doses up to 4,000 mg and multiple daily doses between 250 and 1000 mg three times daily in healthy volunteers, valrocemide is absorbed rapidly and is eliminated with a half-life of 6.4 to 9.4 hours (8,9). The Cl/F is in the range of 4.3 to 6.8 L/h, and the volume of distribution (Vss/F) is 48 to 83 L. The pharmacokinetics of valrocemide appears to be linear over the explored dose range.

Approximately 40% of an orally administered dose is excreted in urine as valproyl glycine. During multiple dosing, the renal clearance of unchanged drug is in the order of 1.2 to 1.4 L/h and the formation clearance of valproyl glycine is approximately 2.4 to 2.7 L/h. The fraction of valrocemide metabolized to valproic acid in healthy subjects, assessed by calculating the ratio between the plasma valproic acid AUC after oral administration of valrocemide and the plasma valproic acid AUC (derived from literature data) after direct administration of valproate, has been estimated to be approximately 4% to 6% (9).

Drug Interactions.

Epileptic patients comedicated with phenytoin, carbamazepine, and other anticonvulsants show higher Cl/F values (mean, 8.2 L/h) and shorter half-lives (mean, 4.7 hours) compared with healthy subjects. This suggests that valrocemide metabolism is stimulated by enzyme-inducing antiepileptic comedication. In patients not receiving enzyme-inducing anticonvulsants, valrocemide kinetics are similar to those observed in healthy volunteers (9).

In human liver microsomes, clinically relevant concentrations of valrocemide and valproyl glycine have no inhibitory effect on the activity of CYP1A2, CYP2C9, CYP2C19,CYP2D6, CYP2E2, CYP3A4, and epoxide hydrolase.

Tolerability Data in Humans.

In a 13-week tolerability study in 22 epileptic patients, valrocemide was well tolerated in general (9). Twenty-one patients completed the study, with 14 patients achieving the maximum allowed dose of 2,000 mg twice daily. Most commonly observed adverse effects affected the CNS or the gastrointestinal system. Of 15 patients with three or more seizures per month at baseline, 2 remained seizure free for the duration of the study.

REFERENCES

1. Armand V, Rundfeldt C, Heinemann U. Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by low magnesium in rat entorhinal cortex hippocampal slices. Epilepsia2000;41;28-33.
2. Armand V, Rundfeldt C, Heinemann U. Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by 4-aminopyridine in rat entorhinal cortex hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol1999; 359:33-39.
3. Bannan PE, Graham DI, Lees KR, et al. Neuroprotective effect of remacemide hydrochloride in focal ischaemia in the cat. Brain Res1994;664:271-275.
4. Bebin M, Black TP. New anticonvulsant drugs: focus on flunarizine, fosphenytoin, midazolam and stiripentol. Drugs1994;48:153-171
5. Beekman M, Ungard JT, Gasior M, et al. Reversal of behavioral effects of pentylenetetrazole by the neuroactive steroid ganaxolone. J Pharmacol Exp Ther1998;285:868-877.
6. Belelli D, Bolger MB, Gee KW. Antiepileptic profile of the progesterone metabolite, 5α-pregnan-3α-ol-20-one. Eur J Pharmacol1989;166:325-329.
7. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: A summary of the Third Eilat Conference. Epilepsy Res1996;25:299-319.

P.925

 

8. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: A summary of the Fourth Eilat Conference (EILAT IV). Epilepsy Res1999;34:1-41.
9. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: A summary of the fifth Eilat conference (EILAT IV). Epilepsy Res2001;43:11-58.
10. Biber A, Dienel A. Pharmacokinetic of losigamone, a new antiepileptic drug, in healthy male volunteers. Int J Clin Pharmacol Ther1996;34:6-11.
11. Bleakman D, Ballyk BA, Schoepp DD, et al. Activity of 2,3-benzodiazepines at native rat and recombinant human glutamate receptors in vitro: stereospecificity and selectivity profiles. Neuropharmacology1996;35:1689-1702.
12. Blotnick S, Bergman F, Bialer M. The disposition of valproyl glycinamide and valproyl glycine in rats. Pharm Res1997;14:873-878.
13. Borowicz KK, Luszczki J, Szadkowski M, et al. Influence of LY 300164, an antagonist of AMPA/kainate receptors, on the anticonvulsant activity of clonazepam. Eur J Pharmacol1999;380: 67-72
14. Borowicz KK, Kleinrok Z, Czuczwar SJ. The AMPA/kainate receptor antagonist, LY 300164, increases the anticonvulsant effects of diazepam. Naunyn Schmiedebergs Arch Pharmacol2000;361:629-635.
15. Carter RB, Wood PL, Wieland S, et al. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective high-affinity steroid modulator of the GABA_Areceptor. J Pharmacol Exp Ther 1997;280:1284-1295.
16. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy A randomized placebo-controlled syndrome-dedicated trial. Lancet2000;356:1638-1642.
17. Clark B, Hutchison JB, Jamieson V, et al.. Potential antiepileptic drugs: remacemide hydrochloride. In: Levy RH, Mattson RH, Meldrum B, eds. Antiepileptic drugs,4th ed. New York: Raven Press, 1995:1035-1044.
18. Craig CR. Antiepileptic activity of steroids: separability of antiepileptic from hormonal effects. J Pharmacol Exp Ther1966;153:337-343.
19. Crawford P, Richens A, Mawer G, et al. A double-blind placebo controlled cross-over study of remacemide hydrochloride as adjunctive therapy in patients with refractory epilepsy. Epilepsy Res1992;1[Suppl A]:7-13.
20. Czuczwar SJ, Swiader M, Kuzniar H, et al. LY 300164, a novel antagonist of AMPA/kainate receptors, potentiates the anticonvulsive activity of antiepileptic drugs. Eur J Pharmacol1998; 359:103-109.
21. Dailey JW, Cheong JH, Ko KH, et al. Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response. Neurosci Lett1995;195:77-80.
22. Dailey JW, Adams-Curtis LE, Ryu JR, et al. Neurochemical correlates of antiepileptic drugs in the genetically epilepsy-prone rat (GEPR). Life Sci1996;58:259-266.
23. Dimpfel W, Chatterjee SS, Noldner M, et al. Effects of the anticonvulsant losigamone and its isomers on the GABAA receptor system. Epilepsia1995;36:983-989.
24. Dienel A, Biber A. Losigamone: comprehensive summary of safety and tolerability in volunteers. Epilepsia1996;37[Suppl 4]:63-64.
25. Dost R, Rundfeldt C. The anticonvulsant retigabine potently suppresses epileptiform discharges in the low Ca++ and low Mg++ model in the hippocampal slice preparation.Epilepsy Res1999;38:53-66.
26. Draguhn A, Jungclaus M, Sokolowa S, et al. Losigamone decreases the spontaneous synaptic activity in cultured hippocampal neurons. Eur J Pharmacol1997;325:245-251.
27. Elger CE, Stefan H, Runge U, et al. Losigamone, double-blind study of 1,500 mg/day versus placebo in patients with focal epilepsy. Epilepsia1996;37[Suppl 4]:64.
28. Fariello RG, McArthur RA, Bonsignori A, et al. Preclinical evaluation of PNU-151774E as a novel anticonvulsant. J Pharmacol Exp Ther1998;285:397-403.
29. Fariello RG, Maj R, Marrari P, et al. Acute behavioral and EEG effects of NW-1015 on electrically-induced afterdischarge in conscious monkeys. Epilepsy Res2000;39:37-46.
30. Farwell JR, Anderson GD, Kerr B, et al. Stiripentol in atypical absence seizures in children: an open trial. Epilepsia1993;34: 305-311.
31. Garske GE, Palmer GC, Napier JJ, et al. Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat. Epilepsy Res1991;9:161-174.
32. Gasior M, Carter RB, Goldberg SR, et al. Anticonvulsant and behavioural effects of neuroactive steroids alone and in conjunction with diazepam. J Pharmacol Exp Ther1997;282: 543-553.
33. Gatti G, Bonomi I, Jannuzzi G, et al. The new antiepileptic drugs: pharmacological and clinical aspects. Curr Pharm Design2000;6:839-860.
34. Gee KW, McCauley LD, Lan NC. A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.Crit Rev Neurobiol1995;9:207-227.
35. Gillardin JM, Verleye M, Ralambosoa C, et al. Anticonvulsant profile and plasma-brain concentrations of a new 2,6-dimethyl-benzamide-N-(5-methyl-3-isoxazolyl)(D2916) in rats. Epilepsia1993;34[Suppl 6]:38.
36. Greenamyre JT, Eller RV, Zhang Z, et al. Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson's disease.Ann Neurol1994;35:655-661.
37. Hadad S, Bialer M. Pharmacokinetic analysis and antiepileptic activity of N-valproyl derivatives of GABA and glycine. Pharm Res1995;12:1160-1163.
38. Harr JE, Maher GG, Kunze KL, et al. Predictions of drug interactions based on identification of CYP450 isoforms which metabolize and are inhibited by D2916, a novel anticonvulsant. Presented at the Meeting of the American Association of Pharmaceutical Scientists, Seattle, WA, October 28-31, 1996.
39. Hetka R, Rundfeldt C, Heinemann U, et al. Retigabine (D-23129) strongly reduces repetitive firing in rat entorhinal cortex. Eur J Pharmacol1999;386:165-171.
40. Hudzik TJ, Freedman L, Palmer GC. Remacemide hydrochloride and ARL 15896AR lack abuse potential: additional differences from other uncompetitive NMDA antagonists.Epilepsia1996;37:544-550.
41. Jones MW, Blume W, Guberman A, et al. Remacemide hydrochloride (300mg, 600mg, 800 mg/day) efficacy and safety versus placebo in patients with refractory epilepsy.Epilepsia1996;37[Suppl 5]:166.
42. Jones FA, Davies JA. The anticonvulsant effects of the enantiomers of losigamone. Br J Pharmacol1999;128:1223-1228.
43. Kapetanovic IM, Rundfeldt C. D-23129: A new anticonvulsant compound. CNS Drug Rev1996;2:308-321.
44. Kapetanovic IM, Yonekawa WD, Kupferberg HJ. The effect of anticonvulsant compounds on 4-aminopyridine-induced de novosynthesis of neurotransmitter amino acids in rat hippocampus in vitro. Epilepsy Res 1995;20:113-120.
45. Kapetanovic IM, Yonekawa WD, Kupferberg HJ. D-23129 stimulated de novosynthesis of GABA in rat hippocampal slices is blocked by an inhibitor of the Na+/K+ antiporter.Epilepsia 1996;37[Suppl 5]:81
46. Kerr BM, Martinez-Lage JM, Viteri C, et al. Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome P450 inhibition by stiripentol. Epilepsia1991;32: 267-274

P.926

 

47. Kerrigan JF, Shields WD, Nelson TY, et al. Ganaxolone for treating intractable infantile spasms: a multicentre, open-label, add-on trial. Epilepsy Res2000;42:133-139.
48. Kohr G, Heinemann U. Anticonvulsant effects of tetronic acid derivatives on picrotoxin-induced epileptiform activity in rat hippocampal slices. Neurosci Lett1990;112:43-47.
49. Kohr G, Heinemann U. Effects of tetronic acid derivatives AO-33 (losigamone) and AO-78 on epileptiform activity and on stimulus-induced calcium concentration changes in rat hippocampal slices. Epilepsy Res1990;7:49-55.
50. Konitsiotis C, Blanchet PJ, Verhagen L, et al. AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkey. Neurology2000;54:1589-1595.
51. Krämer G, Wad N, Bredel-Geissler A, et al. Losigamone-phenytoin interaction: a placebo-controlled, double-blind study in healthy volunteers. Epilepsia1995;36[Suppl 3]:S163.
52. Krämer G, Wad N, Bredel-Geissler, et al. Losigamone-valproate interaction: a placebo-controlled, double-blind study in healthy volunteers. Epilepsia1995;36[Suppl 4]:53.
53. Krämer G, Wad N, Bredel-Geissler A, et al. Losigamone interactions with antiepileptic drugs in healthy volunteers. Epilepsia1996;37[Suppl 4]:89.
54. Kupferberg HJ. Sodium valproate. Adv Neurol1980;27:643-654.
55. Laxer K, Blum D, Abou-Khalil B, et al. Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design. Epilepsia2000;41:1187-1194
56. Leach JP, Blacklaw J, Jamieson V, et al. Mutual interaction between remacemide hydrochloride and carbamazepine: two drugs with active metabolites. Epilepsia1996;37:1100-1106.
57. Leach JP, Girvan J, Jamieson V, et al. Mutual interaction between remacemide hydrochloride and phenytoin. Epilepsy Res1997;26:381-388.
58. Leach JP, Blacklaw J, Jamieson V, et al. Mutual interaction between remacemide hydrochloride and carbamazepine: two drugs with active metabolites. Epilepsia1996;37:1100-1106
59. Lechtenberg R, Villeneuve N, Monagham EP, et al. An open-label dose-escalation study to evaluate the safety and tolerability of ganaxolone in the treatment of refractory epilepsy in pediatric patients. Epilepsia1996;37[Suppl 5]:204.
60. Lepage F, Tombret F, Cuvier G, et al. New N-aryl isoxazolecarboxamides and N-isoxazolylbenzamides as anticonvulsant agents. Eur J Med Chem1992;27:581-593.
61. Lepage F, Gillardin JM, Tombret F, et al. Human and rat metabolism of D2916 and anticonvulsant properties of its metabolites. Epilepsia1995;36[Suppl 4]:49.
62. Levy RH, Lin HS, Blehaut H, et al. Pharmacokinetics of stiripentol in normal man: evidence of nonlinearity. J Clin Pharmacol1983;23:523-533.
63. Levy RH, Loiseau P, Guyot M, et al. Stiripentol kinetics in epilepsy: nonlinearity and interactions. Clin Pharmacol Ther1984;36:661-669.
64. Levy RH, Loiseau P, Guyot M, et al. Effects of stiripentol on valproate plasma level and metabolism. Epilepsia1987;28:605.
65. Liptakova S, Velisek L, Veliskova J, et al. Effect of ganaxolone on fluorothyl seizures in developing rats. Epilepsia2000;41:788-793.
66. Lockard JS, Levy RH, Rhodes PH, et al. Stiripentol in acute/chronic efficacy tests in monkeys model. Epilepsia1985;26: 704-712.
67. Lodge D, Bond A, O'Neill MJ, et al. Stereoselectivity effects of 2,3-benzodiazepines in vivo: electrophysiology and neuroprotection studies. Neuropharmacology1996;35:1681-1688.
68. Loiseau P, Duche B. Potential antiepileptic drugs: stiripentol. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs,4th ed. New York: Raven Press, 1995:1045-1056.
69. Main MJ, Cryan JE, Dupere JR, et al. Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol2000;58:253-262.
70. Maj R, Fariello RG, Ukmar G, et al. PNU-151774E protects against kainate-induced status epilepticus and hippocampal lesions in the rat. Eur J Pharmacol1998;359:27-32.
71. Maj R, Fariello RG, Pevarello P, et al. Anticonvulsant activity of PNU-151774E in the amygdala kindled model of complex partial seizures. Epilepsia1999;40:1523-1528.
72. May PC, Robison PM, Fuson KS. Stereoselective neuroprotection by novel 2,3 benzodiazepine non-competitive AMPA antagonist against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures. Neurosci Lett1999; 262:219-221..
73. Micheletti G, Vergnes M, Lannes B, et al. Effect of stiripentol on petit-mal like epilepsy in Wistar rats. Epilepsia1988;29:709.
74. Monagham EP, Densel MB, Lechtenberg R. Gender differences in sensitivity to ganaxolone, a neuroactive steroid under investigation as an antiepileptic drug. Epilepsia1996;37[Suppl 5]:171.
75. Monagham EP, Navalta LA, Shum L, et al. Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity. Epilepsia1997;38:1026-1031.
76. Moreland TA, Astoin J, Lepage F. The metabolic fate of stiripentol in man. Drug Metab Dispos1986;14:654-662.
77. Muir KT, Palmer GC. Remacemide. In: Pisani F, Perucca E, Avanzini G, et al., eds. New antiepileptic drugs.Amsterdam: Elsevier Science, 1991:147-152.
78. Nakao N, Grasbon-Frodl EM, Widner H, et al. DARPP-32-rich zones in grafts of lateral ganglionic eminence govern the extent of functional recovery in skilled paw reaching in an animal model of Huntington's disease. Neuroscience1996;74: 959-970.
79. Palmer GC, Stagnitto ML, Ordy JM, et al. Preclinical profile of stereoisomers of the anticonvulsant remacemide in mice. Epilepsy Res1991 ;8:36-48.
80. Palmer GC, Murray RJ, Wilson TCM, et al. Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide. Epilepsy Res1992;12:9-20.
81. Palmer GC, Harris EW, Ray R, et al. Classification of compounds for prevention of NMDLA-induced seizures/mortality or maximal electroshock and pentylenetetrazol seizures in mice and antagonism of MK-801 binding in vitro. Arch Int Pharmacodyn Ther1992;317:16-34.
82. Perez J, Chiron C, Musial C, et al. Stiripentol: efficacy and tolerability in epileptic children. Epilepsia1999;40:1618-1626.
83. Perucca E. The new generation of antiepileptic drugs: advantages and disadvantages. Br J Clin Pharmacol1996;42:531-543.
84. Perucca E. Drugs under clinical trial. In: Eadie MJ, Vajda FJE, eds. Antiepileptic drugs: pharmacology and therapeutics. Handbook of experimental pharmacology,vol 138. Berlin: Springer-Verlag, 1999:515-551.
85. Pevarello P, Bonsignori A, Dostert P, et al. Synthesis and anticonvulsant activity of a new class of 2-[(arylalkyl)amino]alkanamide derivatives. J Med Chem1998;41:579-590.
86. Poisson M, Huguet F, Savatier A, et al. A new type of anticonvulsant, stiripentol. Arzneimittelforschung1984;34:199-204.
87. Rey E, Tran A, D'Athis P, et al. Stiripentol potentiates clobazam in childhood epilepsy: a pharmacological study. Epilepsia1999;40[Suppl 7]:112-113.
88. Riley RJ, Slee D, Martin CA, et al. In vitro evaluation of pharmacokinetic interactions between remacemide hydrochloride and established anticonvulsants. Br J Clin Pharmacol1996;41:461P
89. Rostock A, Tober G, Rundfeldt C, et al. D-23129: a new anticonvulsant with a broad spectrum of activity in animal models of epileptic seizures. Epilepsy Res1996;23:211-223.
90. Rostock A, Bartsch R, Engel J. D-23129, a new anticonvulsant improves learning and memory in rat models of cerebral deficiency. Epilepsia1996;37[Suppl 4]:140.
91. Rostock A, Tober C, Dost R., et al. AWD 131-138. Drugs Future1998;23:253-255.

P.927

 

92. Rostock A, Tober C, Dost R, et al. AWD 131-138 is a potential novel anxiolytic without sedation and amnesia: a comparison with diazepam and buspirone. Naunyn Schmiedebergs Arch Pharmacol1998;358[Suppl 1]:R68.
93. Rostock A, Rundfeldt C, Bartsch R. Effect of the anticonvulsant retigabine in neuropathic pain models. Naunyn Schmiedebergs Arch Pharmacol2001 (in press).
94. Rostock A., Tober C, Rundfeldt C, et al. D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res2000;23:211-223.
95. Rundfeldt C. The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. Eur J Pharmacol1997;336:243-249.
96. Rundfeldt C. Characterization of the K+ channel opening effect of the anticonvulsant retigabine in PC 12 cells. Epilepsy Res1999;35:99-107.
97. Rundfeldt C, Roeper J, Netzer R. AWD 131-138 antagonizes the effect of corticotrophin releasing factor in locus coeruleus neurones in murine brain stem slices. Naunyn Schmiedebergs Arch Pharmacol1999;359[Suppl 3]:R97.
98. Rundfeldt C, Netzer R. The novel anticonvulsant retigabine activates M-currents in chinese hamster ovary-cells transfected with human KCNQ2/3 subunits. Neurosci Lett2000;282:73-76.
99. Runge U, Rabending G, Dienel A. Losigamone: preliminary efficacy with 1,500 mg fixed daily dose for >6 months in patients with focal epilepsy. Epilepsia1996;37[Suppl 4]:75.
100. Salvati P, Maj R, Caccia C, et al. Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. J Pharmacol Exp Ther1999; 288:1151-1159.
101. Schaffler K, Wauschkuhn CH, Dienel A, et al. Losigamone has a longer CNS bioavailability in volunteers than is expected from pharmacokinetics. Epilepsia1996;37[Suppl 4]:159.
102. Scheyer RD, Cramer JA, Leppik IE, et al. Remacemide elimination after initial and chronic dosing. Clin Pharmacol Ther1992;51:189.
103. Schmitz D, Gloveli T, Heinemann U. Effects of losigamone on synaptic potentials and spike frequency habituation in rat entorhinal cortex and hippocampal CA1 neurons.Neurosci Lett1995;200:141-143.
104. Schroeder BC, Kubisch C, Stein V, et al. Moderate loss of function of cyclic-AMP modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature1998;396,687-690.
105. Spiegelstein O, Yagen B, Bialer M. Structure-pharmacokineticpharmacodynamic relationships of the new antiepileptic drug valproyl glycinamide. Epilepsia1999;40:545-552.
106. Srivanasan J, Richens A, Davies JA. Losigamone reduces glutamate and aspartate release from mouse cortex. Br J Pharmacol1996;117[Suppl]:164P.
107. Stagnitto ML, Palmer GC, Ordy JM, et al. Preclinical profile of remacemide: a novel anticonvulsant effective against maximal electroshock seizures in mice. Epilepsy Res1990;7:11-28.
108. Stein U. Potential antiepileptic drugs: losigamone. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs,4th ed. New York: Raven Press, 1995:1025-1034.
109. Stein U, Klessing K, Chatterjee SS. Losigamone. In: Pisani F, Perucca E, Avanzini G, et al., eds. New antiepileptic drugs.Amsterdam: Elsevier Science, 1991:129-133.
110. Straub H, Köhling R, Speckmann E-J, et al. Retigabine suppresses epileptiform activity in human neocortical slice preparations. Epilepsia1999;40[Suppl 2]:38.
111. Strolin Benedetti M, Marrari P, Colombo M, et al. The anticonvulsant FCE 26743 is a selective and short-acting MAO-B inhibitor devoid of inducing properties towards cytochrome P450-dependent testosterone hydroxylation in mice and rats. J Pharm Pharmacol1994;46:814-819.
112. Tober C, Rostock A, Rundfeldt C, et al. D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures. Eur J Pharmacol1996;303:163-169.
113. Tober C, Rostock A, Bartsch R. AWD 131-138: a derivative of a series of imidazolinones with anticonvulsant activity. Naunyn Schmiedebergs Arch Pharmacol1998;358[Suppl 1]:R68.
114. Tober C, Rostock A, White HS, et al. Anticonvulsant activity of AWD 131-138 in genetic animal models of epilepsy. Naunyn Schmiedebergs Arch Pharmacol1999;359[Suppl 3]:R97.
115. Torchin CD, McNeilly PJ, Kapetanovic IM, et al. Stereoselective metabolism of a new anticonvulsant drug candidate, losigamone, by human liver microsomes. Drug Metab Dispos1996; 24:1002-1008.
116. Torchin CD, Yonekawa WD, Kapetanovic IM, et al. Chiral high-performance liquid chromatographic analysis of enantiomers of losigamone, a new candidate antiepileptic drugs. J Chromatogr B Biomed Sci Appl1999;724:101-108.
117. Van den Bosch L, Vandenberghe W, Klaassen H, et al. Ca⁺⁺permeable AMPA receptors and selective vulnerability of motor neurons. J Neurosci 2000;180:290-334.
118. Wad N, Kramer G. Losigamone: detection of its glucuronide in serum. Epilepsia1997;38[Suppl 3]:148.
119. Walton NY, Treiman DM. Remacemide versus phenytoin for treatment of experimental status epilepticus. Epilepsia1997;37 [Suppl 5]:212.
120. Walton NY, Jaing Q, Hyun B, et al. Lamotrigine vs phenytoin for treatment of status epilepticus: comparison in an experimental model. Epilepsy Res1996;24:19-28.
121. Wamil AW, Cheung H, Harris EW, et al. Remacemide HCl and its metabolite, AR-C 12495AA, limit action potential firing frequency and block NMDA responses of mouse spinal cord neurons in cell culture. Epilepsy Res1996;23:1-14.
122. Wang HS, Pan Z, Shi W, et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science1998;282:1890-1893.
123. Wang L, Vieth R, Landes RC, et al. Antiepileptic effect of antiepilepsirine in pentylenetetrazol and amygdala kindled rats. Epilepsy Res1993;15:1-5.
124. Wang L, Walson PD, Zuo CH. Clinical and experimental evaluation of anti-epilepsirine. Epilepsia1997;38[Suppl 3]:101.
125. Wang L, Zhao D, Zhang Z, et al. Trial of antiepilepsirine in children with epilepsy. Brain Dev1999;21:36-40.
126. White HS, Armstrong H, Barton M, et al. Anticonvulsant profile of NPS 1776: a broad-spectrum anticonvulsant. Epilepsia1999;40[Suppl 7]:28.
127. Yan QS, Mishra PK, Burger RL, et al. Evidence that carbamazepine anriepilepsirine may produce a component of their anticonvulsant effects by activating serotonergic neurons in genetically epilepsy-prone rats. J Pharmacol Exp Ther1992;261:652-659.
128. Yasar S, Paronis C, Munzar P, et al. Evaluation of the antiepileptic drug AWD 131-138 for reinforcing and discriminative stimulus effects. Behav Pharmacol1999;10[Suppl 1]:103.
129. Yonekawa WD, Kapetanovic IM, Kupferberg HJ. The effects of anticonvulsant agents on 4-aminopyridine induced epileptiform activity in rat hippocampus in vitro. Epilepsy Res1995;20: 137-150.
130. Zhang CL, Chatterjee SS, Stein U, et al. Comparison of the effects of losigamone and its isomers on maximal electroshock-induced convulsions in mice and on three different patterns of low magnesium induced epileptiform activity in slices of the rat temporal cortex. Naunyn Schmiedebergs Arch Pharmacol1992; 345:85-92.