Synergistic interaction between valproate and lamotrigine against seizures induced by 4-aminopyridine and pentylenetetrazole in mice.
We compared the effects of adding a non-protective dose of valproate to increasing doses of lamotrigine with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by both 4-aminopyridine and 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 valproate against 4-aminopyridine and pentylenetetrazole but not on rotarod, the protective index being increased from 1.1 to 2.4 against 4-aminopyridine and from 1.9 to 3.8 against pentylenetetrazole, without changes in brain valproate, and with a significant increase in brain GABA. Valproate increased the potency ratio of lamotrigine against 4-aminopyridine but not on rotarod, the protective index being increased from 4.4 to 7.3; valproate also increased brain lamotrigine (but only at low doses), brain GABA and brain glutamate. In conclusion, non-protective doses of lamotrigine increased the therapeutic index of valproate and vice versa, and these effects appeared to be pharmacodynamic.
Cuadrado
Antonio
A
Clinical Pharmacology Service, Marqués de Valdecilla University Hospital, Department of Physiology and Pharmacology, University of Cantabria School of Medicine, Avda de Valdecilla, s/n, E-39008, Santander, Spain.
de las Cuevas
Isabel
I
Valdizán
Elsa M
EM
Armijo
Juan A
JA
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D014227:Triazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*
D014227:Triazines; D014635:Valproic Acid; D000077213:Lamotrigine; D010433:Pentylenetetrazole