Is the interaction between felbamate and valproate against seizures induced by 4-aminopyridine and pentylenetetrazole in mice beneficial?
We compared the effects of adding a non-protective dose of valproate (VPA) to increasing single doses of felbamate (FBM) with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by 14 mg kg(-1) of 4-aminopyridine (4-AP) and by 110 mg kg(-1) of pentylenetetrazole (PTZ), and neurotoxicity by the rotarod test. The study also assessed changes in concentrations of anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate in the whole brain. VPA increased the potency ratio of FBM against 4-AP (1.94, P<0.05) but not against PTZ. VPA increased the neurotoxicity of FBM (3.30, P<0.05) and the protective index of FBM was, therefore, reduced from 12.0 to 7.0 for the 4-AP model and from 11.8 to 5.2 for the PTZ model; VPA reduced brain FBM, and increased brain GABA in relation to FBM monotherapy. On the other hand, FBM increased the potency ratio of VPA against 4-AP (1.60, P<0.05) but not against the PTZ, and had no effect on the rotarod model. Therefore, the protective index increased from 1.1 to 1.6 for the 4-AP model and decreased from 1.9 to 1.7 for the PTZ model. FBM did not change brain VPA, and changes in brain GABA and glutamate were not clearly related to anticonvulsant effects. In conclusion, although the addition of a low dose of FBM to VPA was beneficial in the 4-AP model, the addition of a low dose of VPA to FBM was not; both combinations were disadvantageous in the PTZ model. This interaction appears to be pharmacodynamic because a pharmacokinetic mechanism was discarded.
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.
Amat
Gaspar
G
Armijo
Juan A
JA
D015761:4-Aminopyridine; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000078328:Felbamate; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020258:Neurotoxicity Syndromes / Q000188:drug therapy; D010433:Pentylenetetrazole; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D018675:Toxicity Tests; D014635:Valproic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D048448:Phenylcarbamates; D011409:Propylene Glycols; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D015761:4-Aminopyridine; D010433:Pentylenetetrazole; D000078328:Felbamate