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 eva...

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Bibliographic Details
Published in:European journal of pharmacology 2002-10, Vol.453 (1), p.43-52
Main Authors: Cuadrado, Antonio, de las Cuevas, Isabel, Valdizán, Elsa M, Armijo, Juan A
Format: Article
Language:English
Subjects:
4-Aminopyridine
Animals
Anticonvulsant
Anticonvulsants. Antiepileptics. Antiparkinson agents
Biological and medical sciences
Brain - drug effects
Brain - metabolism
Dose-Response Relationship, Drug
Drug interactions
Drug Synergism
Drug Therapy, Combination
Lamotrigine
Male
Medical sciences
Mice
Neuropharmacology
Pentylenetetrazole
Pentylenetetrazole - toxicity
Pharmacology. Drug treatments
Seizures - chemically induced
Seizures - drug therapy
Seizures - physiopathology
Triazines - pharmacokinetics
Triazines - therapeutic use
Valproate
Valproic Acid - pharmacokinetics
Valproic Acid - therapeutic use
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Summary: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, γ-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.
ISSN:0014-2999
1879-0712
DOI:10.1016/S0014-2999(02)02341-5