losigame and Epilepsy

Losigamone is a potential antiepileptic under development by Schwabe, which is currently in phase III clinical trials. By August 2000, Schwabe was seeking suitable partners to collaborate in the completion of the phase III trials and further development. The exact mode of action of losigamone is unclear but it does not involve specific binding of GABA, flunitrazepam or t-butyl-bicyclophosphorothionate (TBPS) to their receptors. Data concerning the interaction of losigamone with GABA-A receptor channels, however, are inconsistent; it does not significantly modify the GABAergic inhibitory postsynaptic potentials (IPSPs) in hippocampal slices, although it potentiates GABA-induced chloride influx in primary spinal cord neuron cultures. Another suggested possible mechanism of action for losigamone is K+ channel activation.

Topics: Anticonvulsants; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Epilepsy; Furans; Humans; Structure-Activity Relationship

Topics: Animals; Anticonvulsants; Brain; Drugs, Investigational; Electroencephalography; Epilepsy; Evoked Potentials; Furans; Humans; Rats

The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED(50add)) was 138 mg/kg, while the experimentally derived ED(50) for the mixture (ED(50mix)) was 85.2 mg/kg. The difference was significant at p<0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED(50add)=18.4 mg/kg versus ED(50mix)=26.7 mg/kg, p<0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED(50), however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED(50) values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the importance of measuring AED concentrations in studies designed to identify desirable AED combinations.

Topics: Animals; Anticonvulsants; Brain; Brain Chemistry; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroshock; Epilepsy; Furans; Mice

Losigamone (AO-33) is a recemate of a tetronic acid derivative. The effects of losigamone and its three isomers (AO-242, AO-294 and AO-23) were compared on maximal electroshock (MES) induced convulsions in mice and on different patterns of extracellularly recorded, low Mg2+ induced epileptiform activity in slices of the rat temporal cortex. Lowering Mg2+ induced recurrent short discharges in areas CA3 and CA1 while ictaform events that lasted for many seconds were induced in the entorhinal cortex. In the hippocampus the activity stayed stable over a number of hours. In contrast, the ictaform events in the entorhinal cortex changed their characteristics after one to two hours to recurrent discharges of 0.8 to 10 s. Afterdischarges and interictal events were absent. 50 microM AO-242 showed a similar efficacy to 50 microM AO-33 in reducing and blocking epileptiform discharges in areas CA1 and CA3 while 50 microM AO-294 and 50 microM AO-23 had weaker effects than 50 microM AO-33. Concentrations of 50 microM and 100 microM AO-242 showed a similar efficacy to AO-33 on ictaform events in the entorhinal cortex. Late recurrent discharges were also blocked by AO-33 and AO-242 although at higher concentrations (300 microM). The in vitro observations are with respect to order of efficacy in accordance with the in vivo data obtained in the maximal electroshock test in mice. The order of potency in the MES test was AO-242 greater than AO-33 much greater than AO-294 much greater than AO-23.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Cerebral Cortex; Electrophysiology; Electroshock; Epilepsy; Furans; Hippocampus; Magnesium; Male; Mice; Seizures; Stereoisomerism

We have investigated the effects of a new class of anticonvulsants, the tetronic acid derivatives AO33 (generic name: losigame) and AO78, on field potentials, extracellular calcium concentration changes and intracellular potentials in rat hippocampal slices treated with the non-competitive GABAA antagonist picrotoxin (PTX). The tetronic acid derivatives reduced and eventually blocked spontaneous epileptiform events, induced by 10 to 30 microM PTX. Stimulus induced burst discharges were shortened in duration, but not blocked. Extracellular calcium concentration changes and associated slow negative field potentials were diminished in a dose dependent manner. Intracellular recordings revealed no effect of AO33 on resting membrane potential, little effect on input resistance, a small increase in the threshold of action potentials and an attenuation of stimulus induced paroxysmal depolarisation shifts (PDSs). Spontaneous PDSs initially decreased in duration until they were no longer observable.

Topics: Action Potentials; Animals; Anticonvulsants; Epilepsy; Female; Furans; Hippocampus; In Vitro Techniques; Picrotoxin; Rats; Rats, Inbred Strains