Update on novel antiepileptic drugs

Emerging Drugs ISSN: 1361-9195 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/iemd19 Update on novel antiepileptic drugs MC Walker & PN Patsalos To cite this article: MC Walker & PN Patsalos (1997) Update on novel antiepileptic drugs, Emerging Drugs, 2:1, 381-395, DOI: 10.1517/14728214.2.1.381 To link to this article: http://dx.doi.org/10.1517/14728214.2.1.381 Published online: 24 Feb 2005. Submit your article to this journal Article views: 12 View related articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iemd19 Download by: [Fudan University] Date: 23 February 2017, At: 03:22 Emerging Drugs: The Prospect for Improved Medicines Annual Executive Briefing 1997 Chapter Seventeen Update on Novel Antiepileptic Drugs MC Walker & PN Patsalos Emerging Drugs (1997) 2:381-393 Summary Epilepsy is the most common serious neurological condition. Approximately 20% of patients with epilepsy are resistant to current antiepileptic drugs (AEDs), and newly licensed AEDs have not significantly changed the prognosis for this group. New AEDs are thus still needed to treat this refractory group. Although established AEDs have been very successful in treating epilepsy, they are associated with frequent adverse events, and newer AEDs with better side-effect profiles may eventually replace the older drugs as first-line therapy. There has, however, been caution in using new AEDs as first-line treatment because of questions of long-term safety and cost. As well as treating epilepsy, there is a need for drugs that prevent the development of epilepsy following, for example, head injury. None of the established AEDs has been shown to achieve this, but newer drugs have been found to be anti-epileptogenic in animal models. Whether this is so in the clinical situation has yet to be established. This is a potentially large under-investigated market. Although new AEDs have largely been developed through widespread screening in animal epilepsy models and the modification of existing compounds, there has been a growth in the rational development of AEDs. Drugs that increase brain γ-aminobutyric acid (GABA) concentrations have now become well-established, and a new drug, tiagabine, that operates via this mechanism is shortly to be launched in a number of countries. Research has recently been concentrated on the development of drugs whose antiepileptic effect is mediated through glutamate receptors. Initial investigation of N-methyl-D-aspartate (NMDA) receptor antagonists in patients with epilepsy was disappointing, but drugs that act via non-NMDA glutamate receptors, and metabotropic glutamate receptors look promising. Background Epilepsy is the propensity to have seizures and is one of the most common serious neurological conditions, affecting 0.4 - 1% of the population [1]. There are approximately 381 ©Ashley Publications Ltd. ISSN 1361 - 9195 382 Update on Novel Antiepileptic Drugs - Walker & Patsalos 20 - 70/100,000 new cases per year, and the life-time risk of developing epilepsy is 3 - 5% [1]. In the UK, the annual cost per patient has been estimated to be £4167 (US$6251) for active epilepsy (a seizure in the last 2 years), decreasing to £1630 (US$2445) for inactive epilepsy (no seizures for 2 years) [2]. Most of this cost (70 - 80%) consists of indirect (social) costs such as unemployment, underemployment and excessive mortality [2]. The cost of AED treatment itself comprises only a small percentage (6%) of the direct costs of epilepsy (health care and residential care costs) [2]. Approximately 70 - 80% of patients with epilepsy are successfully treated with present AEDs, and over half of these will be able to stop treatment successfully [3]. This leaves approximately 20 - 30% who have epilepsy resistant to present antiepileptic medication, and very few of these patients (5 - 10%) are suitable for epilepsy neurosurgery. Recently launched AEDs, which are initially licensed for use in this refractory group, have had little impact, possibly rendering fewer than 2% of this group seizure free [4]. Effective novel AEDs are still required for treatment of those with refractory epilepsy, approximately 0.15% of the general population. Even in those in whom established AEDs are effective, side-effects commonly restrict their use. Indeed, in comparative drug studies in newly diagnosed patients, there is more often a difference in treatment failure due to drug side-effects rather than lack of efficacy [5]. Improving the tolerability of AEDs is a second and important aim. A third aspect is that of prognosis. There has been evidence to suggest that early AED treatment favourably alters the prognosis of epilepsy, yet there is a growing body of evidence, mainly from untreated populations in developing countries, to suggest that present AED treatment has little or no influence on the prognosis of epilepsy. Indeed, the prognosis of a patient with epilepsy is likely to relate to the underlying cause of the epilepsy and a number of other factors that have yet to be identified [3]. Furthermore, there is substantial evidence that established AEDs have no effect when used as prophylaxis to prevent the occurrence of epilepsy following head injury or neurosurgery [6]. Novel agents are thus required: to treat patients with refractory epilepsy, to improve AED tolerability, to prevent epileptogenesis, and to improve the prognosis of epilepsy. Currently available AEDs can best be divided into established AEDs and new AEDs. Established AEDs have the advantages of good and proven efficacy, and known chronic and acute side-effects. Their main disadvantage lies in their frequently unacceptable side-effects, and this is especially so with the older AEDs, phenobarbitone and phenytoin [7]. Furthermore most established AEDs have imperfect pharmacokinetics leading to drug interactions, difficulties in dose titration and frequent dosing that may lead to poor compliance, a major cause of AED treatment failure [8]. In some cases, the pharmacokinetic profiles of AEDs have been improved by the use of slow release preparations (i.e., slow release carbamazepine and valproate). ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 Chapter Seventeen - Emerging Drugs 1997 383 It is possible to differentiate AEDs by their mode of action. However, most AEDs have been developed by screening of compounds using in vivo and more recently in vitro models of epilepsy [9]. This has led to the development and marketing of AEDs with unknown modes of action. Current research goals Short-term goals Short term goals are centred around the development of novel AEDs with proven efficacy in refractory epilepsy and to improve the pharmacokinetic profile of AEDs. • The development of novel AEDs with specific physiological targets • The identification of compounds with efficacy in a wide range of different epilepsies • The development of AEDs with no drug interactions, simple kinetics, minimal metabolism and which require once to twice daily administration • Research to identify new and better animal models of seizures • Research to identify the mechanisms underlying AED resistance and seizure generation Long-term research goals The long-term research goals are to develop novel AEDs that can compete with established AEDs for use in newly diagnosed patients, and to develop AEDs that improve the prognosis of epilepsy and that prevent epileptogenesis. Competitive environment Table 1 reviews marketed AEDs. Table 2 reviews AEDs in development. ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 384 Update on Novel Antiepileptic Drugs - Walker & Patsalos Table 1: Competitive environment. Marketed antiepileptic drugs. Company Carter-Wallace Warner-Lambert Warner-Lambert Glaxo Wellcome Product Felbamate Fosphenytoin Gabapentin Lamotrigine Structure NH2 O O HO OH O P O Cl NH2 Cl N O N O HO O H2N N H O O N N NH2 NH2 Phase Launched Patent priority US-4868327 19/09/89 Source IDdb Comments Although effective and safe in Phase II/III studies, post-marketing surveillance in the US has revealed a high incidence of aplastic anaemia and the possibility of acute liver failure resulting in restrictions to its licence [10-12]. In addition to its antiepileptic effect, felbamate also exhibits a neuroprotective effect against ischaemia, status epilepticus and traumatic neuronal injury [13-15]. ©Ashley Publications Ltd. All rights reserved. Launched Launched Launched DE-2460891 01/07/76 CA1133938 19/10/82 IDdb IDdb IDdb This is a water soluble pro-drug for phenytoin developed for use as an iv. or im. injection. It can be used as a direct substitute for oral phenytoin when oral administration is not possible [16]. It has fewer local reactions (phlebitis) and possible serious cardiac reactions than intravenous phenytoin [17,18]. Although designed as a GABA agonist, this drug has a completely different, novel mechanism of action [19]. It has a specific binding site in brain that may relate to its antiepileptic activity, and this may be a specific subunit of voltage dependent calcium channels [20]. Other compounds with similar structures bind to this gabapentin-specific binding site and this may provide a new approach to the development of antiepileptic drugs [21]. Initially licensed for use as adjunctive treatment for partial epilepsy, but has recently had its licence in the UK extended to include its use as monotherapy. Clinical experience with this drug now indicates that doses and serum concentrations many times those achieved in the clinical trials are sometimes necessary and are sometimes well tolerated [22]. Emerging Drugs 1997 Chapter Seventeen - Emerging Drugs 1997 385 Table 1: Competitive environment. Marketed antiepileptic drugs (continued). Company Novartis (Ciba-Geigy) McNeil Hoechst Marion Roussel Dainippon Product Oxcarbazepine Topiramate Vigabatrin Zonisamide Structure O N O NH2 O S O O O HO NH2 OH NH2 N O O O O O S O Phase Launched Patent priority NH2 Launched Launched US-4513006 23/04/85 US-3960927 01/06/76 Launched Source IDdb IDdb IDdb IDdb Comments A pro-drug which is a modification of an established drug (carbamazepine) in order to improve pharmacokinetic (fewer drug interactions) and tolerability profiles [8]. This is the most recently marketed AED in the UK. It has multiple mode of actions including a novel mode of action on GABA receptors, and a possible action at non-NMDA receptors [23]. In the trials there was a large withdrawal rate and incidence of adverse events, which may have been related to the rapid titration used [24]. This is an irreversible GABA transaminase inhibitor, which via this mechanism increases brain GABA. It has been widely and successfully used as adjunctive treatment for partial epilepsy, but has been hampered by reports of depression and psychosis which may be side-effects common to this class of drug [25]. Retrospective data have suggested that vigabatrin can be considered an initial treatment in infantile spasms, a refractory seizure type in infants [26]. Vigabatrin may also have a neuroprotective role [27]. Marketed in Japan since 1989, but development was held up in Europe and US because of a high incidence of renal stones not seen in Japanese patients [28]. ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 386 Update on Novel Antiepileptic Drugs - Walker & Patsalos Table 2: Competitive environment. Antiepileptic drugs in development. Company Union Chimique Belge Dr Wilmar Schwabe Fisons Novo Nordisk Product Levetiracetam Losigamone Remacemide Tiagabine Structure O H3C O H 2N CH 3 N O HO S O O Cl H N H2N O S H3C N OH O Phase Phase II Phase II/III Phase II/III Phase III EP-279937 31/08/88 Patent priority Source IDdb IDdb IDdb IDdb Comments This was developed as a cognition enhancing agent as one of a number of ‘nootropic’ drugs. It has been shown to exert powerful anticonvulsant effects in a wide variety of seizure models in rats and mice. It has been relatively free of neurotoxic effects in rats up to a dose of 50 times the ED50 [29]. Its mechanism of action is unknown; a specific binding site in the central nervous system (CNS) has been found, but has yet to be characterised [30]. Very effective against electrically- and chemically-induced seizures in animals with encouraging preliminary studies in humans. Mechanism of action is at present unknown [31]. Losigamone does not bind to GABA, benzodiazepine (BZD) or picrotoxin binding sites, but it activates the GABA-sensitive chloride channel at a site distant from the GABA-A channel [32]. Probably a pro-drug for its more efficacious metabolites, which act on NMDA receptors both at glycine-sensitive and non-competitive binding sites [8]. First of a line of clinically useful GABA uptake inhibitors, developed by producing lipophilic derivatives of nipecotic acid (a GABA uptake inhibitor that does not cross the blood-brain barrier) [33]. There are plans to file the drug in Europe and the US. ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 Chapter Seventeen - Emerging Drugs 1997 387 Editorial analysis Medical need There continues to be a need for new AEDs to treat those with pharmaco-resistant epilepsy. Although the market for these drugs is smaller than the market for established AEDs, the cost of new AEDs compared to established AEDs has meant that this market is equally lucrative. A recent study has shown that two recently marketed new AEDs, vigabatrin and lamotrigine, have not significantly changed the prognosis in terms of mortality or seizure freedom of patients with severe refractory epilepsy [34]; furthermore, very few patients continued these drugs long-term [34]. An initial boom in sales followed by a significant fall would thus be expected with the eventual annual market being almost equivalent to the incident market (approximately 10% of the prevalent market). This does, however, leave a potentially large market for further effective new AEDs. The size of the potential market could be increased by encouraging the earlier use of new antiepileptic drugs in less refractory patients, but this would require demonstrating a definite advantage over more established AEDs for use as second-line treatment. In addition, new AEDs with better pharmacokinetic profiles and better tolerability than the established AEDs may prove useful in the treatment of newly diagnosed, drug-naive patients. This potential application meets with two particular hurdles. • Initial new AED trials are carried out as adjunctive medication in patients with refractory epilepsy (usually partial epilepsy), and are only later assessed as monotherapy and in other types of epilepsy. The licence for new AEDs is therefore usually initially restricted to those with pharmaco-resistant partial epilepsy. • Even when new AEDs are later licensed for use as monotherapy (e.g., lamotrigine in the UK), they are not commonly used as first-line therapy. This is due to the chronic adverse events for these drugs being unknown, and their high relative cost (over 10 times the cost of treatment with established drugs). Furthermore, because of the limited numbers of patients included in trials, rare but clinically significant adverse events can be missed and would only come to light with post-marketing surveillance. The problems that have occurred with the widespread use of the new AED felbamate (aplastic anaemia and hepatic toxicity) have resulted in further caution in the licensing and use of new AEDs. Antiepileptic drug development The strategies for AED development are: screening novel compounds in animal models of epilepsy, modulating the structure of known AEDs, and targeting specific physiological substrates [9]. Screening is imprecise as many thousands of compounds have to be screened in order to identify suitable candidates. It has, however, been responsible for most AED ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 388 Update on Novel Antiepileptic Drugs - Walker & Patsalos development. It is also limited by the appropriateness of the epilepsy models used. A number of compounds that have been very effective in certain animal models of epilepsy have had poor efficacy in patients with epilepsy. Conversely, it is likely that a number of compounds that have been rejected as suitable candidates for AED development due to their impotency in animal epilepsy models might have been efficacious in human epilepsy. Structural modification of existing AEDs has been a successful method of improving side-effect profiles and pharmacokinetics. The established AEDs are limited by both their side-effects and their pharmacokinetics. Modification of these drugs has achieved a certain amount of success. Slow-release compounds have resulted in less frequent dosing with fewer fluctuations in drug plasma concentrations - leading, in the case of carbamazepine, to greater efficacy and fewer side-effects [8]. Oxcarbazepine, a pro-drug for monohydroxycarbazepine (MHC), is another example of a modification of carbamazepine. MHC does not undergo epoxidation, and it is the epoxide metabolite of carbamazepine that is felt to contribute substantially to some of the side-effects of carbamazepine [8]. Furthermore oxcarbazepine has fewer and less extensive drug interactions than carbamazepine. In addition to developing AEDs with better peripheral pharmacokinetics, procedures have been developed to improve the specific central nervous system uptake of AEDs. Thus chemical delivery systems have been designed based on dihydropyridine-pyridinium salt type targetors [35]. This involves converting a drug into a 1,4-dihydropyridine moiety, which is highly lipophilic and thus easily passes the blood-brain barrier. It is then rapidly oxidised to form the hydrophilic pyridinium salt, which is eliminated from the periphery but is ‘locked’ in the CNS. The active drug is then slowly released by enzymatic hydrolysis [35]. Targeting specific physiological substrates would seem the most rational and efficient method of AED development and has been responsible for the development of vigabatrin and tiagabine. It has, however, met with considerable difficulties. Irreversible antagonists at NMDA receptors (a glutamate receptor involved in the pathophysiology of epilepsy) have had potent anticonvulsant activity in animal models, but have proved to have unacceptable side-effects with poor efficacy in patients with epilepsy. SDZ-EAA-494 is an example of this. Furthermore, while doses of 2000 mg/day of SDZ-EAA-494 were well tolerated by human volunteers, lower doses (500 - 1000 mg/day) resulted in serious side-effects in patients [36]. Another example of the difficulties in rational drug development is that of milacemide. This was developed as a glycine pro-drug which crosses the blood-brain barrier; glycine was known to be an inhibitory neurotransmitter in the central nervous system. Later, however, glycine was shown to have an effect on the NMDA receptor complex in brain, potentiating the effects of glutamate (i.e., it had a possible pro-convulsant effect) [37]. Any anti-convulsant activity it had in animal models was probably due to its action in increasing brain GABA [38]. Indeed, development of milacemide was halted as it had minimal efficacy in humans. This inefficacy could possibly have been due to a poor understanding of its pharmacokinetics ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 Chapter Seventeen - Emerging Drugs 1997 389 which probably resulted in sub-therapeutic doses being administered to patients during its clinical evaluation [39]. Another miscomprehension occurred in the development of lamotrigine, which was devised to have antifolate properties due to the misconception that the efficacy of some established AEDs was via that mechanism. Lamotrigine ironically has minimal antifolate properties, and its mechanisms of action are completely unconnected to this [40]. However, with a growing understanding of different receptor classes and of the roles of these in epilepsy, newer drugs are now being developed that target specific receptors. Of growing interest has been the increasing literature on the antiepileptic effects of drugs that act at specific glutamate receptors. NMDA receptor antagonists have until recently been the main target for research, but have proved to be ineffective clinically (see above). Potent antiepileptic activity in animal models has, however, also been shown by drugs that act at non-NMDA glutamate receptors (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]/kainate receptors), such as the 2,3-benzodiazepines [41], and it is likely that such drugs will lack the adverse psychological effects of NMDA receptor antagonists. These drugs will be entering Phase I studies soon. Other drugs with non-NMDA glutamate receptor targets are also being developed [42,43]. Ligands at metabotropic glutamate receptors have been demonstrated to have antiepileptic activity [44,45], but their role in epilepsy is still being evaluated. Antagonists at different glutamate receptors appear to have different roles in the prevention of epileptogenesis and seizures [46]. NMDA receptors but not non-NMDA receptors appear to play a key role in the kindling process - the development of epilepsy in animals through the application of subthreshold stimulation. Expression of seizures, on the other hand, involves both non-NMDA and NMDA receptors [46]. Although NMDA antagonists have disappointed in their role as antiepileptic drugs, there may be role for them in the prevention of the development of epilepsy. This is important as established AEDs have failed to prevent the occurrence of epilepsy following head injuries or neurosurgery [47,48]. This is a poorly developed area, and agents that prevent the development of epilepsy following head injury, stroke and neurosurgery would have a potentially large market. Concluding summary Novel AEDs are mainly aimed at treating patients with refractory epilepsy, and improving upon existing AED treatments. In view of costs and clinical experience the former is the more realistic aim, although the effect of novel AEDs on the prognosis of epilepsy in this group has been disappointing. Other treatment modalities such as epilepsy neurosurgery have had only a small impact on refractory epilepsy. Most AEDs have been developed by screening compounds in animal models or modulating the structure of known AEDs. Screening of compounds has been limited by the range and precision of animal models of human epilepsy. The modulation of known AEDs has been very successful especially in improving their pharmacokinetic profiles. Rational development of compounds with particu©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 390 Update on Novel Antiepileptic Drugs - Walker & Patsalos lar physiological targets is a growing field which has yet to achieve its potential, and which has led to many compounds that have floundered at the clinical stage. There continues to be a need for agents that prevent epileptogenesis following cerebral insults. This is a poorly researched area, and results from animal models have yet to be confirmed in humans. So far no antiepileptic drug has demonstrated efficacy in this potentially large market. The further development of novel AEDs is very much dependent on advances in our understanding of the molecular mechanisms underlying epilepsy, and in the production of better and more precise models of human epilepsy. Bibliography Papers of special note have been highlighted as: • of interest •• of considerable interest 1. • SANDER JW, SHORVON SD: Incidence and prevalence studies in epilepsy and their methodological problems: a review. J. Neurol. Neurosurg. Psychiatry (1987) 50:829-839. A comprehensive review of the epidemiology of epilepsy worldwide with a special emphasis on methodological problems that can result in spurious results. 2. •• COCKERELL OC, HART YM, SANDER JWAS, SHORVON SD: The cost of epilepsy in the United Kingdom: an estimation based on the results of two population-based studies. Epilepsy Res. (1994) 18:249-260. A thorough estimation of the cost of epilepsy, both in terms of direct and indirect costs. 3. •• SANDER JW: Some aspects of prognosis in the epilepsies: a review. Epilepsia (1993) 34:1007-1016. An excellent review of all aspects of the prognosis of epilepsy. 4. •• WALKER MC, SANDER JWAS: The impact of new antiepileptic drugs on the prognosis of epilepsy: seizure freedom should be the ultimate goal. Neurology (1996) 46:912-914. A controversial review considering the outcome measures that should be used in antiepileptic drug trials, and the relatively disappointing impact of new antiepileptic drugs on the prognosis of epilepsy. 5. MATTSON RH, CRAMER JA, COLLINS JF et al.: Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondary generalised tonic-clonic seizures. New Engl. J. Med. (1985) 313:145-151. 6. WALKER MC, SANDER JWAS: Overtreatment with antiepileptic drugs: how extensive is the problem? CNS Drugs (1994) 2(5):335-340. 7. • PATSALOS PN, SANDER JWAS: Newer antiepileptic drugs: towards an improved risk-benefit ratio. Drug Safety (1994) 11:37-67. A thorough review of new antiepileptic drugs. 8. •• WALKER MC, PATSALOS PN: Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol. Ther. (1995) 67:351-384. A thorough review of new antiepileptic drug pharmacokinetics with a proposed scoring system which emphasises those aspects of the pharmacokinetics which are clinically important. 9. •• LOSCHER W, SCHMIDT D: New drugs for the treatment of epilepsy. Curr. Opin. Invest. Drugs (1993) 2(10):1067-1095. ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 Chapter Seventeen - Emerging Drugs 1997 391 An excellent review of antiepileptic drug development, including animal models and mechanisms of action. 10. PENNELL PB, OGAILY MS, MACDONALD RL: Aplastic anemia in a patient receiving felbamate for complex partial seizures. Neurology (1995) 45:456-460. 11. O’NEIL MG, PERDUN CS, WILSON MB, MCGOWN ST, PATEL S: Felbamate-associated fatal acute hepatic necrosis. Neurology (1996) 46:1457-1459. 12. BEBIN EM, SOFIA RD, DREIFUSS FE: Felbamate: toxicity. In: New Antiepileptic Drugs (4th Edition). Levy RH, Mattson RH, Meldrum BS (Eds.), Raven Press, New York (1995):823-827. 13. WALLIS RA, PANIZZON KL: Felbamate neuroprotection against CA1 traumatic neuronal injury. Eur. J. Pharmacol. (1995) 294:475-482. 14. CHRONOPOULOS A, STAFSTROM C, THURBER S et al.: Neuroprotective effect of felbamate after kainic acid-induced status epilepticus. Epilepsia (1993) 34:359-366. 15. WASTERLAIN CG, ADAMS LM, SCHWARTZ PH et al.: Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia-ischemia. Neurology (1993) 43:2303-2310. 16. WILDER BJ, CAMPBELL K, RAMSAY RE et al.: Safety and tolerance of multiple doses of intramuscular fosphenytoin substituted for oral phenytoin in epilepsy or neurosurgery. Arch. Neurol. (1996) 53:764-768. 17. JAMERSON BD, DUKES GE, BROUWER KL et al.: Venous irritation related to intravenous administration of phenytoin versus fosphenytoin. Pharmacotherapy (1994) 14:47-52. 18. RAMSAY RE, DETOLEDO J: Intravenous administration of fosphenytoin: options for the management of seizures. Neurology (1996) 46:S17-19. 19. TAYLOR CP: Emerging perspectives on the mechanism of action of gabapentin. Neurology (1994) 44(Suppl. 5):S10-16. 20. GEE NS, BROWN JP, DISSANAYAKE VU et al.: The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J. Biol. Chem. (1996) 271:5768-5776. 21. TAYLOR CP, VARTANIAN MG, YUEN PW et al.: Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labeled by tritiated gabapentin. Epilepsy Res. (1993) 14:11-15. 22. KILPATRICK ES, FORREST G, BRODIE MJ: Concentration-effect and concentration-toxicity relations with lamotrigine: a prospective study. Epilepsia (1996) 37:534-538. 23. BEN-MENACHEM E: Topiramate. In: New Antiepileptic Drugs (4th Edition). Levy RH, Mattson RH, Meldrum BS (Eds.), Raven Press, New York (1995):1063-1070. 24. WALKER MC, SANDER JWAS: Topiramate: a new antiepileptic drug for refractory epilepsy. Seizure (1996) 5:199-204. 25. RING HA, TRIMBLE MR, COSTA DC et al.: Effect of vigabatrin on striatal dopamine receptors: evidence in humans for interactions of GABA and dopamine systems. J. Neurol. Neurosurg. Psychiatry (1992) 55:758-761. 26. AICARDI J, MUMFORD JP, DUMAS C, WOOD S: Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer Review Groups. Epilepsia (1996) 37:638-642. 27. • PITKANEN A: Treatment with antiepileptic drugs: possible neuroprotective effects. Neurology (1996) 47:S12-16. ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 392 Update on Novel Antiepileptic Drugs - Walker & Patsalos A paper describing the possible neuroprotective effects of antiepileptic drugs given prior to status epilepticus. This may be important as it has been suggested that seizures themselves may produce neuronal damage, and thus drugs that prevent this damage may improve the prognosis in some epilepsy syndromes. 28. WALKER MC, SANDER JW: Developments in antiepileptic drug therapy. Curr. Opin. Neurol. (1994) 7:131-139. 29. GOWER AJ, NOYER M, VERLOES R, GOBERT J, WULFERT E: UCB L059, a novel anti-convulsant drug: pharmacological profile in animals. Eur. J. Pharmacol. (1992) 222:193-203. 30. NOYER M, GILLARD M, MATAGNE A, HENICHART JP, WULFERT E: The novel antiepileptic drug levetiracetam (UCB L059) appears to act via a specific binding site in CNS membranes. Eur. J. Pharmacol. (1995) 286:137-146. 31. STEIN U, KLESSING K, CHATTERJEE SS: Losigamone. Epilepsy Res. Suppl. (1991) 3:129-133. 32. DIMPFEL W, CHATTERJEE SS, NOLDNER M, TICKU MK: Effects of the anticonvulsant losigamone and its isomers on the GABA-A receptor system. Epilepsia (1995) 36:983-989. 33. • ANDERSEN KE, BRAESTRUP C, GRONWALD FC et al.: The synthesis of novel GABA uptake inhibitors.1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate. J. Med. Chem. (1993) 36:1716-1725. An interesting paper demonstrating how different synthetic approaches can lead to different drug candidates and the basis on which the final choice is made. 34. • WALKER MC, LI LM, SANDER JWAS: Long term use of lamotrigine and vigabatrin in severe refractory epilepsy: audit of outcome. Br. Med. J. (1996) 313:1184-1185. The results of this audit suggest that the newer antiepileptic drugs have no effect on the prognosis of severe refractory epilepsy. 35. •• POP E, BODOR N: Chemical systems for delivery of antiepileptic drugs to the central nervous system. Epilepsy Res. (1992) 13:1-16. This paper describes a method of improving antiepileptic drug penetration into the central nervous system and by this means possibly improving their efficacy. 36. • SVEINBJORNSDOTTIR S, SANDER JW, UPTON D et al.: The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res. (1993) 16:165-174. A study in which a drug that was well tolerated in healthy volunteers had unacceptable adverse events in patients with epilepsy. 37. JOHNSON JW, ASCHER P: Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature (1987) 325:529-531. 38. DE VAREBEKE JP, NIEBES P, PAUWELS G, ROBA J, KORF J: Effect of milacemide, a glycinamide derivative, on the rat brain gamma-aminobutyric acid system. Biochem. Pharmacol. (1983) 32:2751-2755. 39. • SEMBA J, CURZON G, PATSALOS PN: Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: milacemide. Br. J. Pharmacol. (1993) 108:1117-1124. An important study demonstrating how an understanding of an antiepileptic drug’s neuropharmacokinetics can explain its inefficacy in clinical trials. 40. SANDER JW, PATSALOS PN: An assessment of serum and red blood cell folate concentrations in patients with epilepsy on lamotrigine therapy. Epilepsy Res. (1992) 13:89-92. 41. DE SARRO G, CHIMIRRI A, DE SARRO A et al.: GYKI 52466 and related 2,3-benzodiazepines as anticonvulsant agents in DBA/2 mice. Eur. J Pharmacol. (1995) 294:411-422. ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997 Chapter Seventeen - Emerging Drugs 1997 393 42. SHIMIZU-SASAMATA M, KAWASAKI-YATSUGI S et al.: YM90K: pharmacological characterization as a selective and potent alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist. J. Pharmacol. Exp. Ther. (1996) 276:84-92. 43. OHMORI J, KUBOTA H, SHIMIZU-SASAMATA M, OKADA M, SAKAMOTO S: Novel alphaamino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonists: synthesis and structureactivity relationships of 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3-b]pyrazinedione and related compounds. J. Med. Chem. (1996) 39:1331-1338. 44. DALBY NO, THOMSEN C: Modulation of seizure activity in mice by metabotropic glutamate receptor ligands. J. Pharmacol. Exp. Ther. (1996) 276:516-522. 45. MONN JA, VALLI MJ, JOHNSON BG et al.: Synthesis of the four isomers of 4-aminopyrrolidine2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. J. Med. Chem. (1996) 39:2990-3000. 46. • DURMULLER N, CRAGGS M, MELDRUM BS: The effect of the non-NMDA receptor antagonist GYKI 52466 and NBQX and the competitive NMDA receptor antagonist D-CPPene on the development of amygdala kindling and on amygdala-kindled seizures. Epilepsy Res. (1994) 17:167-174. A paper describing the different effects of specific glutamate receptor antagonists on the development of epilepsy, and seizures. 47. • TEMKIN NR, DIKMEN SS, WILENSKY AJ et al.: A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. New Engl. J. Med. (1990) 323:497-502. A paper showing the inefficacy of phenytoin in preventing the development of late epilepsy following head trauma. 48. • FOY PM, CHADWICK DW, RAJGOPALAN N, JOHNSON AL, SHAW MDM: Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy? J. Neurol. Neurosurg. Psychiatry (1992) 55:753-757. A paper demonstrating the inefficacy of both carbamazepine and phenytoin as prophylaxis following craniotomy. MC Walker† & PN Patsalos †Author for correspondence Epilepsy Research Group, Pharmacology and Therapeutics Unit, Institute of Neurology, Queen Square, London WC1N 3BG ©Ashley Publications Ltd. All rights reserved. Emerging Drugs 1997