Real-world evaluation of perampanel effectiveness in Japanese adolescents with epilepsy

Objective: Real-world data from adolescents treated with perampanel in a routine clinical setting are lacking in Japan. We evaluated the safety and efficacy of perampanel for adolescent patients (aged 12-17 years) with drug-resistant, refractory epilepsy in real-world settings. Methods: This was a large-scale, prospective, observational post-marketing study, with a 104-week observation period. Safety was assessed by monitoring adverse effects (adverse drug reactions). For efficacy assessments, seizure frequency was compared between the four weeks immediately prior to the last observation and the four weeks before the commencement of perampanel. Results: In total, 519 patients were enrolled; 505 and 484 patients were included in the safety and efficacy analysis sets, respectively. The mean age was 14.4 years. The mean daily dose of perampanel was 4.4 mg/day. The main reasons for discontinuation at 104 weeks were adverse events (48.4%) and inadequate efficacy (46.8%). The retention rate at 104 weeks was 50.5%. Adverse effect and severe adverse effect incidences were 42.2% and 1.8%, respectively. The most common adverse effects were somnolence (13.5%), irritability (8.5%), dizziness (5.1%), and agitation (4.8%). There were significant differences in the occurrence of adverse effects between the initial titration interval of <2 weeks and 2-4 weeks (odds ratio=0.441, p=0.029) and 4-8 weeks (odds ratio=0.462, p=0.027). The median percent change in seizure frequency at the last observation carried forward was −50.0 for focal aware seizures with motor signs, −73.3 for focal aware seizures without motor signs, −28.6 for focal impaired awareness seizures, −62.6 for focal to bilateral tonic-clonic seizures, and −20.0 for generalized tonic-clonic seizures. Significance: In adolescent patients, perampanel was well tolerated and efficacious in reducing seizure frequency. No unexpected safety issues were observed, and slow titration may reduce the incidence of adverse effects.

Enantiopure 2-(2-ethylhexyl)dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophenes: synthesis, single-crystal structure and a surprising lack of influence of stereoisomerism on thin-film structure and electronic properties.

Starting from a chiral resolution of 2-ethylhexanoic acid followed by conversions of functional groups without interfering with the enantiopurity, we have successfully introduced an enantiopure 2-ethylhexyl group on to dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT) via a Negishi-coupling reaction to synthesize 2-(R)-(2-ethylhexyl)- and 2-(S)-(2-ethylhexyl)-DNTT (R- and S-EH-DNTT, respectively). Then, the crystallinities, thin-film structures, and the organic field-effect transistors (OFETs) based on R-, S- and racemic EH-DNTT (rac-EH-DNTT) were studied to elucidate the effect of stereoisomerism in the 2-ethylhexyl group. The crystal structures of the R- and S-EH-DNTTs are classified as herringbone packing and contain two crystallographically independent molecules connected by edge-to-face CH-π intermolecular interactions, and the molecules' directly opposite directions avoid steric repulsion between the 2-ethylhexyl groups. Thin films of the EH-DNTTs fabricated using both the spin-coating and vacuum-deposition methods were revealed to have similar but slightly different packing structures to that in the single crystal. Intriguingly, the packing structures in the thin-film state depend on the deposition method, and not on the stereoisomers of EH-DNTT. Consistent with the packing structures in the thin-film state, the performance of OFETs based on the thin films of the R-, S- and rac-EH-DNTTs were affected by the deposition method, and not by the stereoisomerism. This means that the stereoisomerism in the alkyl side chain has a marginal effect on the packing structure and electronic properties in the thin-film state. This is endorsed by the theoretical calculations using the functional-group symmetry-adapted perturbation theory (F-SAPT), which indicated that the intermolecular interactions between the DNTT cores are dominant in the total intermolecular interaction energies, and implies that the crystallization process in the thin-film deposition could be governed by intermolecular interactions between the DNTT cores. We conclude that in 2-ethylhexyl-substituted organic semiconductors with a large and highly aggregative π-conjugated core, like EH-DNTT, the enantiopurity in the 2-ethylhexyl group does not significantly affect the thin-film structure and thus the performance of thin-film OFETs.

Evaluation of real-world effectiveness of perampanel in Japanese adults and older adults with epilepsy.

OBJECTIVE: While previous studies have demonstrated the safety and effectiveness of perampanel (PER) in combination with other anti-seizure medications in adult patients, data for older patients are limited. This study aimed to confirm real-world safety and effectiveness of combination treatment with PER in Japanese patients with focal seizures with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalised tonic-clonic seizures (GTCS) according to age subgroups (<65 and ≥65 years of age). METHODS: This large-sample prospective post-marketing observational study included a 24-52-week observation period after the first PER treatment. Safety was assessed according to adverse drug reactions (ADRs) and efficacy was evaluated based on the 50% responder rate and rates of overall symptom improvement. RESULTS: Among the 3,808 patients who were enrolled, 3,716 (3,026 patients aged <65 years and 690 patients aged ≥65 years) and 3,272 were included in the safety and efficacy analysis datasets, respectively. ADRs were reported for 1,247 patients (33.6%) in the safety analysis dataset. Of these, 36.2% and 22.2% were aged <65 years and ≥65 years, respectively, and the most common ADRs were somnolence (11.6%, 5.5%) and dizziness (9.7%, 5.4%). The 50% responder rates in patients aged <65 years and those ≥65 years were 60.1% and 89.0% for those with focal aware seizures (FAS) with motor signs; 48.0% and 60.0% for FAS without motor signs; 47.4% and 80.2% for focal impaired awareness seizures; 70.8% and 93.4% for FBTCS; and 63.6% and 88.9% for GTCS, respectively. The improvement rates of symptoms/conditions were also higher in patients aged ≥65 years than those <65 years. SIGNIFICANCE: PER was effective in reducing seizure frequency and was safe, especially in older patients. PER may be a clinical treatment option for older patients with seizure disorders.

Disease state changes and safety of long-term donepezil hydrochloride administration in patients with Alzheimer's disease: Japan-Great Outcome of Long-term trial with Donepezil (J-GOLD).

BACKGROUND: A long-term, large-scale study of donepezil hydrochloride in patients with Alzheimer's disease (AD) was conducted. Previously, two interim reports were published during this study. We have now completed the study and herein present our analysis of the final results. METHODS: The subjects of this study included AD patients who received the drug for the first time (newly treated patients), as well as AD patients who were already receiving the drug at the start of the study (continuously treated patients). The observation period was 48 months. Changes in cognitive function and severity of dementia associated with the drug administration and its safety were assessed. RESULTS: Cognitive function decreased significantly after 24 months in newly treated patients and after 6 months in continuously treated patients, compared with baseline. The percentages of patients whose dementia severity improved or remained the same compared with baseline were 59.27% at 48 months in the newly treated patients and 57.09% at 48 months in the continuously treated patients. There were no major safety problems with the drug. CONCLUSIONS: We conducted a large-scale study of AD patients in Japan. Here, we present our analysis of the final results and describe current clinical practice with the drug, changes in cognitive function and dementia severity associated with long-term administration of the drug, and the drug's safety.

Disease state changes and safety of long-term donepezil hydrochloride administration in patients with Alzheimer's disease: interim results from the long-term, large-scale J-GOLD study in Japan.

BACKGROUND: There have been very few long-term studies involving a large study population; existing studies usually have no more than a few hundred patients with Alzheimer's disease. For these reasons, there are no detailed investigations regarding changes in activities of daily living evaluated by the Functional Assessment Staging Test (FAST). METHODS: A long-term, large-scale observational study of donepezil hydrochloride (Aricept(®); Eisai Co., Ltd, Tokyo, Japan) is currently in progress. Its objective is to investigate disease state changes associated with the long-term administration of this drug and its safety in patients with Alzheimer's disease. In this report, data collected over a maximum of 24 months were compiled. Efficacy was assessed using FAST and a cognitive function test (Mini-Mental State Examination or the Hasegawa's Dementia Scale-Revised). RESULTS: The percentages of patients whose FAST stage improved or remained the same compared to at the start of donepezil hydrochloride administration (baseline) were 91.1% at 6 months, 83.0% at 12 months, 79.5% at 18 months, and 74.8% at 24 months. Multivariate logistic regression analysis was conducted to investigate factors that affect the improvement and maintenance or exacerbation of FAST at 24 months. 'Independence level in the daily life of elderly with dementia' and 'duration of illness' were identified as variables that affected the improvement and maintenance or exacerbation of FAST. Cognitive function improved significantly at 12 weeks and at 6 months compared to baseline, maintained baseline levels at 12 months and at 18 months, and decreased significantly at 24 months compared to baseline. CONCLUSIONS: This is the largest prospective study involving Alzheimer's disease patients in Japan, and we believe it is an important study that shows the reality of daily clinical practice.