Losigamone Research Articles

Isobolographic analysis of interactions between losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model

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.

Efficacy and safety of Losigamone in partial seizures: a randomized double-blind study

The objective of the study was to investigate the efficacy and safety of two different dosages of Losigamone (LSG) in add-on treatment of partial seizures. In a multi-center, double-blind, randomized clinical trial, patients received one of three 12-week treatments: placebo, LSG 1200 mg/day, or 1500 mg/day, in addition to up to three standard anticonvulsants after a prospective period of 12 weeks to assess baseline seizure frequency. The primary efficacy measure was the relative reduction of seizure frequency per 4 weeks in the double-blind phase as compared to baseline. In the intention-to-treat population of 264 patients, the relative median reduction of partial seizure frequency was 3.3% for placebo, 19.7% for LSG 1200 mg/day, and 25.3% for LSG 1500 mg/day. The differences of both LSG groups versus placebo were significant ( P<0.01, two-tailed). In the responder analysis, 11.8% of the patients in the placebo group, 17.2% in the LSG 1200 mg/day group, and 29.3% in the LSG 1500 mg/day group showed a seizure reduction versus baseline of at least 50%. A positive association between dosage and response was observed ( P=0.003). Adverse events during treatment were reported by 58.8% of the patients for placebo, by 62.1% for LSG 1200 mg/day and by 76.1% for LSG 1500 mg/day. Most events in the LSG groups occurred during the first 4 weeks of double-blind (during or immediately after up-titration) and subsided quickly. Over the last 4 weeks of treatment, the incidence of adverse events in the LSG groups was close to the placebo level. Based on the study’s results, LSG is an effective and safe add-on drug for refractory partial epilepsy in adults.

Losigamone add-on therapy in partial epilepsy: a placebo-controlled study

To evaluate the efficacy and tolerability of losigamone (LSG). Double-blind, placebo-controlled add-on study with 3x500 mg LSG/die for the treatment of chronic partial seizures in 203 patients (99 treated with LSG, 104 on placebo). The median percent change of seizures was 14.9% (LSG) versus 6.7% (placebo) (P=0.004). Seizure frequency was decreased by more than 50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Mean percent change of seizures was best in patients with only one additional anticonvulsant drug (LSG versus placebo, P=0.004). Adverse events (usually CNS-related side effects of mild to moderate intensity) were reported in 59.6% (LSG) and 37.5% (placebo) of patients. LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures.

Losigamone a putative antiepileptic drug

Losigamone (LSG) has shown anticonvulsant efficacy and low neurotoxicity in preclinical testing and has been tolerated in Phase I clinical trials. We report an open-label, add-on tolerability study of six ascending LSG dosage levels from 600 to 2,100 mg daily in patients receiving phenytoin (PHT), carbamazepine (CBZ), or combination PHT/CBZ. Dosage was escalated weekly, with assessment including reports of adverse events (AE), seizure diary, neurologic and physical examination, electrocardiogram (ECG), and laboratory tests. No serious AE were reported, and those most common AE were headache and dizziness. No significant alteration in PHT, CBZ, or CBZ-epoxide (CBZ-E) levels was noted. No clinically significant change in laboratory tests was noted. A median seizure reduction during LSG treatment as compared with baseline of 39% was achieved during the study. All 9 patients continued into an extension study, and 3 have remained seizure-free for as long as 2 years. Some brief increases in seizure frequency were evident at the 1,800- and 2,100-mg daily dosage levels. We conclude that continued evaluation of LSG for the treatment of partial seizures is indicated.