title: Telemetry video-electroencephalography (EEG) in rats, dogs and non-human primates: methods in follow-up safety pharmacology seizure liability assessments.
abstract: BACKGROUND
  Non-clinical seizure liability studies typically aim to: 1) confirm the nature of EEG activity during abnormal clinical signs, 2) identify premonitory clinical signs, 3) measure plasma levels at seizure onset, 4) demonstrate that drug-induced seizures are self-limiting, 5) confirm that conventional drugs (e.g. diazepam) can treat drug-induced seizures and 6) confirm the no observed adverse effect level (NOAEL) at EEG. Our aim was to originally characterize several of these items in a three species comparative study.
  
  
  METHODS
  Cynomolgus monkey, Beagle dog and Sprague-Dawley rat with EEG telemetry transmitters were used to obtain EEG using the 10-20 system. Pentylenetetrazol (PTZ) was used to determine seizure threshold or as a positive seizurogenic agent. Clinical signs were recorded and premonitory signs were evaluated. In complement, other pharmacological agents were used to illustrate various safety testing strategies.
  
  
  RESULTS
  Intravenous PTZ doses required to induce clonic convulsions were 36.1 (3.8), 56.1 (12.7) and 49.4 (11.7) mg/kg, in Beagle dogs, cynomolgus monkeys and Sprague-Dawley rats, respectively. Premonitory clinical signs typically included decreased physical activity, enhanced physiological tremors, hypersalivation, ataxia, emesis (except in rats) and myoclonus. In Sprague-Dawley rats, amphetamine (PO) increased high (approximately 40-120Hz), and decreased low (1-14Hz) frequencies. In cynomolgus monkeys, caffeine (IM) increased power in high (14-127Hz), and attenuated power in low (1-13Hz) frequencies. In the rat PTZ infusion seizure threshold model, yohimbine (SC and IV) and phenobarbital (IP) confirmed to be reliable positive controls as pro- and anticonvulsants, respectively.
  
  
  CONCLUSIONS
  Telemetry video-EEG for seizure liability investigations was characterized in three species. Rats represent a first-line model in seizure liability assessments. Beagle dogs are often associated with overt susceptibility to seizure and are typically used in seizure liability studies only if required by regulators. Non-human primates represent an important model in seizure liability assessments given similarities to humans and a high translational potential.
authors: CIToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada; Faculty of Veterinary Medicine, Université de Montréal, P.O. box 5000, St.-Hyacinthe, QC J2S 7C6, Canada.
authors: Leanne
authors: L
authors: Bassett
authors: Faculty of Veterinary Medicine, Université de Montréal, P.O. box 5000, St.-Hyacinthe, QC J2S 7C6, Canada.
authors: Eric
authors: E
authors: Troncy
authors: CIToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors: Mylene
authors: M
authors: Pouliot
authors: CIToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors: Dominique
authors: D
authors: Paquette
authors: CIToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors: Alexis
authors: A
authors: Ascah
authors: CIToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada; Faculty of Veterinary Medicine, Université de Montréal, P.O. box 5000, St.-Hyacinthe, QC J2S 7C6, Canada. Electronic address: authiers@ca.citoxlab.com.
authors: Simon
authors: S
authors: Authier
mesh_terms: D000818:Animals; D004285:Dogs; D004569:Electroencephalography; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012449:Safety; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology*; D013686:Telemetry
chemical_list: D010433:Pentylenetetrazole
keywords: Convulsions; EEG spectral analysis; Electromyography/EMG; Premonitory signs; Regulatory drug development; Safety pharmacology; Sedation; Seizure; Telemetry; Tremors