COMPLETING VOLUME 22
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`ISSN 0920-1211
`EPIRES 22(3) 1
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`WESTON liBRARY
`r;~c 2 9 1995
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`. ELSEVI R
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`Vol. 22, No. 3
`NOVEMBER 1995
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`© 1995, Elsevier cience B. V. All rights reserved.
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`ELSEV IER
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`Epilepsy Research 22 (1995) 235- 246
`
`EPILEPSY
`RESEARCH
`
`Conference Review
`Progress report on new antiepileptic drugs
`A summary of the Second Eilat Conference
`J.P. Stables a,• M. Bialer b, S.I. Johannessen c, H.J. Kupferberg a, R.H. Levy d
`P. Loiseau e, E. Perucca r
`
`' Epilepsy Branch. Narionallnsrirure of Neurological Disorders and Srroke, Narionallnsrirwes of Healrh, Berhesda, MD 20892, USA
`b School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
`c Narional Cenrer for Epilepsy, SandL'ika, Norway
`d Deparrmem of Plwrmaceurics, Unh·ersity of Washing ron, Sea/lie. WA, USA
`< Deparrmem of Neurology, Bordeaux Unit·ersity Hospiral Pellegrin, Bordeaux Cedex. France
`r Clinical Plwrmacology Unir. Deparrmem of lmemal Medicine and Therapeurics, Unit·ersity of Pavia. Pal'ia, lraly
`
`Abstract
`
`The Second Eilat Conference on ew Antiepileptic Drugs was held at the King Solomon's Palace Hotel from October 31
`to ovember 3, 1994. Epileptologists and scientists from 20 countries auended the conference, which was held to discuss
`new trial designs, drug approval. early use of new antiepileptic drugs. and new drugs in development. Over the last six years,
`several novel antiepileptic drugs have been introduced worldwide, and new information on their safety and efficacy has
`become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepinc, and vigabatrin. Drugs in development
`include those at an advanced stage, such as topiramate and tiagabine, as well as those just entering clinical trials, such as
`remacemide and levetiracetam. The following is a summary of the presentations for drugs in development and newly
`marketed drugs. The meeting concluded with a presentation, 'Still Searching for the Magic Bullet'.
`
`Keywords: Anticpilcptic drug development; Clinical trial design; Drug approval
`
`1. Topiramate 1
`
`Topiramate
`
`· Corresponding author.
`
`Topiramatc is a sulfamate structura lly unique as
`an antiepilcptic. Several mechanisms have been pro(cid:173)
`posed to explain the manner in which the compound
`exerts its antiepileptic action: (1) blockade of volt(cid:173)
`age-activated sodium channels; (2) enhancement of
`GABA acting at
`the benzodiazepine insensitive
`GABA(A) receptor; and (3) modest blocking action
`at the kainate/ AMPA glutamate receptors. There are
`no known effects at NMDA receptors. Topiramate is
`
`1 Ross A. Reife, Director, Clinical Research C S. The R.W.J.
`Pharmaceutical Research Institute. Spring House, PA; and Lynn
`Kramer. Vice President, Medicine~ and Clinical Development.
`CNS. Cib-Geigy Corp., Basic. Switzerland.
`
`0920-1211/95/$09.50 \C 1995 Elsevier Science B.V. All rights reserved
`SSDI 0920-1211(95)00054-2
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`236
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`J.P. Stables eta/./ Epilepsy Research 22 ( 1995) 235- 2.J6
`
`also a weak carbonic anhydrase inhibitor (about 100
`times weaker than acetazolamide). What effect the
`carbonic anhydrase action has on anticonvulsant ac(cid:173)
`tivity is not clear, but it is directly related to the
`potential to form renal stOnes.
`The pharmacokinetic characteristics of topiramate
`are interesting. It has a high bioavailability (80% of
`an oral dose). It achieves peak plasma concentration
`in 1 to 3 h. Extent of absorption is not affected by
`food, but the presence of food delays absorption by
`approx imately 1 h. The kinetics are dose propor(cid:173)
`tional in the therapeutic dose range. Topiramate is
`only 15% plasma protein bound and predominately
`is excreted unchanged in the urine (80%) when
`administered alone. However, when topiramate is
`administered in conjunction with enzyme-inducing
`anticonvulsants, significant metabolism occurs (up to
`50% of the administered dose). The half life is
`approximately 20 to 30 h but may be shortened
`considerably in the presence of concomitant treat(cid:173)
`ment with enzyme inducers. Topiramate does not
`affect. to a clinically significant extent, the plasma
`levels of concurrent anticonvulsants, except for an
`occasional moderate increase in plasma phenytoin
`levels.
`To date, there have been five completed and
`analyzed multicenter trials (two in the United States
`and three in Europe). These were performed in adults
`as add-on therapy in patients with refractory partial
`onset seizures with or without secondary generaliza(cid:173)
`tion. The dosage range was from 200 to 1000 mg per
`day. Compared with placebo, a statistically signifi(cid:173)
`cant reduction in seizure frequency was observed at
`all dosages; the effect at 200 mg daily reached
`borderline significance. All other efficacy parameters
`(percent of patients with a 50% and with 75% reduc(cid:173)
`tion in seizures, clinician and patient global assess(cid:173)
`ments, reduction in secondarily generalized seizures)
`also showed significant improvements over placebo.
`Since tolerability decreased at dosages above 600 mg
`per day, a dosing range of 200 to 600 mg per day
`(usually in divided doses) is considered optimal in
`most patients. Occasionally some patients may re(cid:173)
`quire higher doses.
`Safety data are based on 1800 patient exposures
`or 2000 subject years. Seventy patients have been
`exposed for more than 5 years. The most common
`
`side effects observed in add-on studies were related
`to the central nervous system. Kidney stones, result(cid:173)
`ing from the carbonic anhydrase effects, have been
`observed in approximately 1.5% of patients. Dose
`and rate of titration are important considerations to
`minimize adverse affects.
`
`2. Tiagabine 2
`
`H
`~COOH
`
`Tiagabine
`
`Tiagabine i a nipecotic acid derivative that cen(cid:173)
`trally inhibits GABA uptake at presynaptic neurons
`and glial cells. It differs from inhibitors of GABA
`transaminase (i.e., vigabatrin) in several ways: (1) Its
`action on GABA is reversible. (2) It causes little or
`no increase in cerebrospinal fluid GABA levels. (3)
`It did not cause intramyelinic edema in animal toxi(cid:173)
`cology studies. (4) It is much better tolerated than
`previously assessed GABA uptake inhibitors such as
`Parke-Davis's CI 966.
`Tiagabine is absorbed rapidly and has linear
`metabolic kinetics. When taken in conjunction with
`food, the rate, rather than the extent of absorption, is
`decreased. The half life in healthy volunteers is 7 h
`but is shortened to approximately 3.5 h in comedi(cid:173)
`cated patient . Therefore, frequent dosing intervals
`
`2 Samuel Berkovic, Dept. of Neurology, Austin Hospital. Mel(cid:173)
`bourne, Australia.
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