title: Functional neurotoxicity evaluation of noribogaine using video-EEG in cynomolgus monkeys.
abstract: BACKGROUND
  Continuous video-electroencephalographic (EEG) monitoring remains the gold standard for seizure liability assessments in preclinical drug safety assessments. EEG monitored by telemetry was used to assess the behavioral and EEG effects of noribogaine hydrochloride (noribogaine) in cynomolgus monkeys. Noribogaine is an iboga alkaloid being studied for the treatment of opioid dependence.
  
  
  METHODS
  Six cynomolgus monkeys (3 per gender) were instrumented with EEG telemetry transmitters. Noribogaine was administered to each monkey at both doses (i.e., 160 and 320mg/kg, PO) with an interval between dosing of at least 6days, and the resulting behavioral and EEG effects were evaluated. IV pentylenetetrazol (PTZ), served as a positive control for induced seizures.
  
  
  RESULTS
  The administration of noribogaine at either of the doses evaluated was not associated with EEG evidence of seizure or with EEG signals known to be premonitory signs of increased seizure risk (e.g., sharp waves, unusual synchrony, shifts to high-frequency patterns). Noribogaine was associated with a mild reduction in activity levels, increased scratching, licking and chewing, and some degree of poor coordination and related clinical signs. A single monkey exhibited brief myoclonic movements that increased in frequency at the high dose, but which did not appear to generalize, cluster or to be linked with EEG abnormalities. Noribogaine was also associated with emesis and partial anorexia. In contrast, PTZ was associated with substantial pre-ictal EEG patterns including large amplitude, repetitive sharp waves leading to generalized seizures and to typical post-ictal EEG frequency attenuation.
  
  
  CONCLUSIONS
  EEG patterns were within normal limits following administration of noribogaine at doses up to 320mg/kg with concurrent clinical signs that correlated with plasma exposures and resolved by the end of the monitoring period. PTZ was invariably associated with EEG paroxysmal activity leading to ictal EEG. In the current study, a noribogaine dose of 320mg/kg was considered to be the EEG no observed adverse effect level (NOAEL) in conscious freely moving cynomolgus monkeys.
authors.affiliation: CiToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada; Faculty of Veterinary Medicine, University of Montreal, P.O. box 5000, St-Hyacinthe, QC J2S 7C6, Canada. Electronic address: authiers@ca.citoxlab.com.
authors.forename: Simon
authors.initials: S
authors.lastname: Authier
authors.affiliation: CiToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Accardi
authors.affiliation: Centre Vétérinaire DMV, 2300 54e Av, Lachine, QC H8T 3R2, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Paquette
authors.affiliation: CiToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors.forename: Mylène
authors.initials: M
authors.lastname: Pouliot
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, USA; Department of Neurology, Albert Einstein College of Medicine, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Arezzo
authors.affiliation: Stubbs & Hensel Pharma Consulting, LLC, PO Box 935, Blue Bell, PA 19422, USA.
authors.forename: R John
authors.initials: RJ
authors.lastname: Stubbs
authors.affiliation: Gerson Pharma Solutions, LLC, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Gerson
authors.affiliation: Pharmaceutical Special Projects Group, LLC, USA.
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Friedhoff
authors.affiliation: DemeRx, Inc., Fort Lauderdale, Florida, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Weis
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003292:Convulsants; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004569:Electroencephalography / Q000187:drug effects*; D005260:Female; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000523:psychology*; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced; D013686:Telemetry
chemical_list: D003292:Convulsants; D007050:Ibogaine; C094385:noribogaine; D010433:Pentylenetetrazole
keywords: Cynomolgus monkey; EEG; Electroencephalography; Noribogaine; Pentylenetetrazol