losigame and Seizures

The new method TISA was used to evaluate Losigamone efficacy.. Sixteen patients with pharmacoresistant partial seizures undergoing presurgical evaluation were randomized in this double-blind, placebo-controlled, parallel-group Losigamone monotherapy study under continuous video-EEG monitoring. Duration (in s, of each seizure and each ictal sign), intensity (grade zero to three), N/24h (number of seizures and ictal signs per 24 h), D/24h (seconds per 24 h covered by seizures and ictal signs) and seizure free intervals were recorded.. A total of 246 seizures were intensively analyzed. The duration and intensity of all seizures improved more in the active treatment group than in the placebo group. There was a statistically significant superiority in the duration of the seizure free interval in the Losigamone group. Ictal signs such as oro-alimentary automatisms and fumbling were improved during Losigamone treatment.. Losigamone has a preferred inhibitory effect on propagated epileptic activity. TISA is a sensitive method for evaluation of the selective effects of AEDs.

Topics: Adult; Anticonvulsants; Double-Blind Method; Electroencephalography; Female; Furans; Humans; Male; Middle Aged; Seizures; Severity of Illness Index; Treatment Outcome

The aim of this study was the isobolographic evaluation of interactions between two enantiomers of losigamone, AO-242 [(+)-5(R)-alpha(S)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone] and AO-294 [(-)-5(S)-alpha(R)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone], and valproate, carbamazepine, phenytoin, or phenobarbital in the maximal electroshock test in mice. Both enantiomers interacted additively with conventional antiepileptic drugs at all studied fixed dose ratios (1:3, 1:1, 3:1). Furthermore, AO-242, AO-294 and antiepileptics applied alone, as well as combinations of enantiomers and antiepileptics did not affect motor performance in the chimney test. Significant impairment of long-term memory (passive-avoidance task) was noted only in the case of valproate alone, given at the dose equal to its median effective dose (ED(50)) against maximal electroshock. All other antiepileptics and their combinations with AO-242 or AO-294 did not impair memory of mice. Enantiomers did not affect the brain concentrations of antiepileptic drugs, indicating a pharmacodynamic nature of the observed interactions. In conclusion, the present results suggest both AO-242 and AO-294 as promising candidate drugs in the add-on therapy of refractory epilepsy.

Topics: Animals; Anticonvulsants; Avoidance Learning; Brain; Carbamazepine; Drug Interactions; Electroshock; Furans; Male; Memory; Mice; Motor Activity; Phenobarbital; Phenytoin; Seizures; Stereoisomerism; Valproic Acid

1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the effects of the S(+)- and R(-)- enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice. 2 S(+)-losigamone (100 and 200 microM) significantly reduced both potassium- and veratridine-elicited release of glutamate and aspartate from cortical slices. R(-)-losigamone had no effect on release at concentrations up to 400 microM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium-free artificial cerebrospinal fluid. S(+)-losigamone significantly reduced these depolarizations at 50-200 microM whilst R(-)-losigamone had a significant effect at 200-800 microM. 4 DBA/2 mice are susceptible to audiogenic seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg-1, i.p.) significantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg-1. There was no protection at 20 mg kg-1 with R(-)-losigamone. 5 These results, from both in vitro and in vivo experiments, confirm that the pharmacological activity profiles of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid-mediated processes are involved in the mode of action of S(+)-losigamone whereas R(-)-losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)-losigamone might therefore be more effective clinically than losigamone or its R(-)-enantiomer.

Topics: Amino Acids; Animals; Anticonvulsants; Cerebral Cortex; Dose-Response Relationship, Drug; Female; Furans; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Potassium; Seizures; Stereoisomerism; Veratridine

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