Isobolographic profile of interactions between tiagabine and gabapentin: a preclinical study.
Combining the use of some antiepileptic drugs (AEDs) in patients with epilepsy can result in interactions of a pharmacodynamic or pharmacokinetic character. To quantify the profile of interactions between tiagabine (TGB) and gabapentin (GBP), two novel AEDs influencing the GABAergic neurotransmitter system, an isobolographic analysis was performed in the maximal electroshock seizure threshold (MEST), pentylenetetrazole (PTZ)-induced seizure and chimney tests in mice. TGB and GBP injected alone dose-dependently raised the electroconvulsive threshold in mice, which allowed the evaluation of TID(20) (the dose increasing the threshold by 20% compared with controls) in the MEST-test. TID(20) values for TGB and GBP alone were 4.3 mg/kg and 70 mg/kg, respectively. On the basis of isobolographic calculations, TGB was also co-administered with GBP at three fixed ratios (1:3, 1:1 and 3:1) of their respective TID(20) doses. The isobolographic analysis showed that all three combinations of TGB with GBP exerted supra-additive (synergistic) interactions in the MEST-test in mice. Likewise, TGB and GBP injected alone suppressed the clonic phase of PTZ-induced seizures, with (effective) doses protecting 50% of the animals tested against clonic convulsions (ED(50)) for TGB and GBP of 0.9 and 199.3 mg/kg, respectively. Moreover, the two-drug combinations at the same fixed ratios of 1:3, 1:1 and 3:1 in PTZ-induced seizures also showed a tendency towards supra-additive (synergistic) interactions. The adverse (neurotoxic) effects produced by TGB and GBP alone or in combinations at the same fixed ratios of 1:3, 1:1 and 3:1 were evaluated in the chimney test. The (toxic) doses evoking motor impairment in 50% of animals tested (TD(50)) for TGB and GBP alone were 13.6 and 979.6 mg/kg, respectively. The isobolographic analysis showed the interactions between the AEDs to be additive in this test. From a preclinical point of view, the interactions observed experimentally showed that the combination of TGB and GBP, due to a synergistic anti-seizure activity of the drugs, might provide adequate seizure control in patients with refractory epilepsy.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland. jarogniew@asklepios.am.lublin.pl
Czuczwar
Stanislaw J
SJ
D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D003292:Convulsants; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004597:Electroshock; D000077206:Gabapentin; D008297:Male; D051379:Mice; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D010433:Pentylenetetrazole; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000588:Amines; D000927:Anticonvulsants; D003292:Convulsants; D003509:Cyclohexanecarboxylic Acids; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D010433:Pentylenetetrazole; D000078308:Tiagabine