Synergistic interaction between felbamate and lamotrigine against seizures induced by 4-aminopyridine and pentylenetetrazole in mice.
We compared the effects of adding a nonprotective dose of felbamate to increasing single doses of lamotrigine with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by both 14 mg/kg of 4-aminopyridine and 110 mg/kg of pentylenetetrazole, and neurotoxic effects were evaluated by the rotarod test. Changes in anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate concentrations in the whole brain were also assessed. Lamotrigine increased the potency ratio of felbamate against 4-aminopyridine (1.80, 95% confidence interval (CI) 1.23-2.65, P<0.05) but not against pentylenetetrazole nor on rotarod, the protective index being increased from 12.0 to 17.1 for 4-aminopyridine, with a reduction in brain felbamate, and with an increase in brain GABA. Felbamate increased the potency ratio of lamotrigine against 4-aminopyridine (4.35, 95% CI 2.05-9.25, P<0.05) but not on rotarod, the protective index being increased from 4.4 to 15.7; there were no changes in brain lamotrigine, and changes in brain GABA and/or glutamate were unrelated to the pharmacodynamic effects. In conclusion, a nonprotective dose of lamotrigine increased the therapeutic index of felbamate and vice versa, and these effects appeared to be pharmacodynamic.
Cuadrado
Antonio
A
Department of Physiology and Pharmacology, Clinical Pharmacology Service, Marqués de Valdecilla University Hospital, University of Cantabria School of Medicine, Avda de Valdecilla, s/n, E-39008 Santander, Spain.
Bravo
Jesús
J
Armijo
Juan A
JA
D015761:4-Aminopyridine / Q000008:administration & dosage; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000078328:Felbamate; D018756:GABA Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D000077213:Lamotrigine; D051379:Mice; D010433:Pentylenetetrazole / Q000008:administration & dosage; D048448:Phenylcarbamates; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D014227:Triazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D018756:GABA Antagonists; D005971:Glutamates; D048448:Phenylcarbamates; D026902:Potassium Channel Blockers; D011409:Propylene Glycols; D014227:Triazines; D005680:gamma-Aminobutyric Acid; D015761:4-Aminopyridine; D000077213:Lamotrigine; D010433:Pentylenetetrazole; D000078328:Felbamate