Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy.
This paper comprises a series of experiments in rodent models of partial and generalized epilepsy which were designed to describe the anti-convulsant profile of the functionalized amino acid lacosamide. Lacosamide was effective against sound-induced seizures in the genetically susceptible Frings mouse, against maximal electroshock test (MES)-induced seizures in rats and mice, in the rat hippocampal kindling model of partial seizures, and in the 6Hz model of psychomotor seizures in mice. The activity in the MES test in both mice (4.5mg/kg i.p.) and rats (3.9 mg/kg p.o.) fell within the ranges previously reported for most clinically available anti-epileptic drugs. At both the median effective dose for MES protection, as well as the median toxic dose for rotorod impairment, lacosamide elevated the seizure threshold in the i.v. pentylenetetrazol seizure test, suggesting that it is unlikely to be pro-convulsant at high doses. Lacosamide was inactive against clonic seizures induced by subcutaneous administration of the chemoconvulsants pentylenetetrazol, bicuculline, and picrotoxin, but it did inhibit NMDA-induced seizures in mice and showed full efficacy in the homocysteine model of epilepsy. In summary, the overall anti-convulsant profile of lacosamide appeared to be unique, and the drug displayed a good margin of safety in those tests in which it was effective. These results suggest that lacosamide may have the potential to be clinically useful for at least the treatment of generalized tonic-clonic and partial-onset epilepsies, and support ongoing clinical trials in these indications.
Stöhr
Thomas
T
Schwarz BioSciences GmbH, Department Pharmacology/Toxicology, Alfred-Nobel Str. 10, 40789 Monheim, Germany. thomas.stoehr@schwarzpharma.com <thomas.stoehr@schwarzpharma.com>
Kupferberg
Harvey J
HJ
Stables
James P
JP
Choi
Daeock
D
Harris
Robert H
RH
Kohn
Harold
H
Walton
Nancy
N
White
H Steve
HS
D000081:Acetamides / Q000009:adverse effects* / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use*; D001640:Bicuculline / Q000494:pharmacology; D003035:Cobalt; D003292:Convulsants; D004597:Electroshock; D004828:Epilepsies, Partial / Q000139:chemically induced / Q000188:drug therapy; D004827:Epilepsy / Q000150:complications / Q000188:drug therapy*; D004829:Epilepsy, Generalized / Q000139:chemically induced / Q000188:drug therapy; D020195:Epilepsy, Reflex / Q000503:physiopathology / Q000517:prevention & control; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006710:Homocysteine; D007696:Kindling, Neurologic / Q000187:drug effects; D000078334:Lacosamide; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000473:pathology; D010433:Pentylenetetrazole; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy
D000081:Acetamides; D000927:Anticonvulsants; D001640:Bicuculline; D003035:Cobalt; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D006710:Homocysteine; D000078334:Lacosamide; D016202:N-Methylaspartate; D010433:Pentylenetetrazole; D010852:Picrotoxin