Epilepsy Research 39 (2000) 37 – 46 Acute behavioral and EEG effects of NW-1015 on electrically-induced afterdischarge in conscious monkeys R.G. Fariello a , R. Maj a, *, P. Marrari b , D. Beard c , C. Algate c , P. Salvati a a Newron Pharmaceuticals SpA, Via Lepetit, 34, I -21040 Gerenzano (VA), Italy b Department Pharmacokinetics and Metabolism, Pharmacia & Upjohn SpA, iale Pasteur, 10, I -20014 Neriano (MI), Italy c Huntingdon Life Science Ltd., PO Box 2, Huntingdon, Cambridgeshire, PE18 6ES UK Received 28 June 1999; received in revised form 10 September 1999; accepted 23 September 1999 Abstract NW-1015 is a novel Na + and Ca 2 + channel blocker with broad spectrum anticonvulsant activity and an excellent safety margin. As the compound also shows sigma-1 receptor ligand properties it was deemed important to determine whether it possesses anticonvulsant properties in primates without causing behavioral and EEG abnormalities. Thus, the effects of NW-1015 on limbic electrically-induced afterdischarge (AD) were evaluated in four cynomolgus monkeys, and its activity compared to a single effective dose of phenytoin (PHT). The four male cynomolgus monkeys were chronically implanted for EEG recordings, from cortex and limbic structures. AD was induced in limbic areas by electrical stimulation. The effects of NW-1015 on the duration and the behavioral component of the AD were randomly tested at doses from 25 to 75 mg/kg and compared with the effects of PHT 50 mg/kg. Similarly to PHT, 50 mg/kg of NW-1015 significantly shortened the EEG AD and almost abolished AD elicited behavioral seizure. Only the behavioral effects of AD were reduced after administration of 25 mg/kg p.o. NW-1015 did not cause EEG or interictal behavioral alterations at doses up to 75 mg/kg p.o. These data further confirm the broad-spectrum anticonvulsant activity and a good safety profile of NW-1015 even in a primate model of complex partial seizures and suggest that its affinity for sigma-1 receptors is behaviorally irrelevant. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Anticonvulsant; NW-1015; Afterdischarge; Epilepsy; Monkeys www.elsevier.com/locate/epilepsyres 1. Introduction Human epilepsies were the first neurological conditions for which an effective pharmacological treatment was provided (Locock, 1857). Indeed, more than a century later, about half a dozen anti-epileptic drugs (AEDs) are used as first line treatment to control seizures and an approxi- mately equal number offer second line alternatives for improving such control (Pellock, 1994; Brodie and Dichter, 1996). Complex partial seizures, also known as temporal lobe or limbic seizures (Porter et al., 1984), are the most frequent and common * Corresponding author. Tel.: +39-2-9668-1323; fax: +39- 2-9668-1333. E-mail address: roberto.maj@newron.it (R. Maj) 0920-1211/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII:S0920-1211(99)00103-5