Anticonvulsant activity of PNU-151774E in the amygdala kindled model of complex partial seizures.
OBJECTIVE
PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a novel antiepileptic drug (AED) with a broad spectrum of activity in a variety of chemically and mechanically induced seizures. The objective of this study was to evaluate the activity of PNU-151774E in the amygdala fully kindled rat model of complex partial seizures, and to compare its effects with those of carbamazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), and gabapentin (GBP), drugs used to treat this disease state.


METHODS
Male Wistar rats were stimulated daily through electrodes implanted in the amygdala with a threshold current until fully generalized seizures developed. The rats were then treated with various doses of a single compound. Control values for each rat and drug dose were determined after vehicle administration followed by electrical stimulation 1 day before drug treatment.


RESULTS
PNU-151774E (1, 10, 30 mg/kg; i.p.) reduced the duration of behavioral seizures significantly and dose-dependently at doses starting from 1 mg/kg. Higher doses significantly reduced seizure severity and afterdischarge duration. In contrast, no dose-related effects were noted after administration of PHT, whereas after CBZ treatment, a plateau of activity was noted from the intermediate to higher doses. The effects of PNU-151774E were comparable to those of LTG and GBP.


CONCLUSIONS
The activity shown by PNU-151774E at doses similar to those that are active in models of generalized seizures indicates that PNU-151774E would also have potential efficacy in the treatment of complex partial seizures.
Maj
R
R
Newron Pharmaceuticals Gerenzano (VA), Italy.
Fariello
R G
RG
Pevarello
P
P
Varasi
M
M
McArthur
R A
RA
Salvati
P
P
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000588:Amines; D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001596:Benzylamines / Q000494:pharmacology* / Q000627:therapeutic use; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D003509:Cyclohexanecarboxylic Acids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017029:Epilepsy, Complex Partial / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000077206:Gabapentin; D007696:Kindling, Neurologic / Q000502:physiology*; D000077213:Lamotrigine; D008297:Male; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D001596:Benzylamines; D003509:Cyclohexanecarboxylic Acids; D014227:Triazines; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D010672:Phenytoin; D000077206:Gabapentin; C092797:safinamide; D000409:Alanine; D000077213:Lamotrigine