Acute behavioral and EEG effects of NW-1015 on electrically-induced afterdischarge in conscious monkeys.
NW-1015 is a novel Na+ and Ca2+ 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.
Fariello
R G
RG
Newron Pharmaceuticals SpA, Gerenzano (VA), Italy.
Maj
R
R
Marrari
P
P
Beard
D
D
Algate
C
C
Salvati
P
P
D000409:Alanine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D001596:Benzylamines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D010672:Phenytoin / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy
D000927:Anticonvulsants; D001596:Benzylamines; D010672:Phenytoin; C092797:safinamide; D000409:Alanine