Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS). METHODS: Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs. RESULTS: In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p < 0.0001) with BRV 50 mg/day and 200 mg/day, respectively, 50% responder rate was 19.0%, 41.1%, and 49.3% with placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p < 0.0001 for both BRV groups vs. placebo). Median percent reduction in FOS frequency from baseline was 21.3%/38.9%/46.7% in patients on placebo/BRV 50 mg/BRV 200 mg/day, respectively. Overall, 0, 7 (4.6%), and 10 (6.8%) patients were classified as seizure-free during the treatment period on placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p = 0.0146/p = 0.0017 for BRV 50 mg/200 mg/day vs. placebo, respectively). TEAE incidences were similar between patients on placebo (58.4%) and all patients receiving BRV (58.5%); TEAE incidences for BRV 50 mg/day and BRV 200 mg/day were 57.0% and 60.1%, respectively. Overall, 0.7% of patients on placebo and 2.0% of all patients on BRV reported serious TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 1.3% and 2.7%, respectively), 20.1% of patients on placebo and 33.1% of all patients on BRV reported drug-related TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 26.5% and 39.9%, respectively), and 4.7% of patients on placebo and 3.0% of all patients on BRV discontinued due to TEAEs (discontinuation incidences for BRV 50 mg/day and BRV 200 mg/day were 2.6% and 3.4%, respectively). SIGNIFICANCE: Adjunctive BRV was efficacious and well tolerated in adult Asian patients with FOS. Efficacy and safety profiles were consistent with BRV studies in predominantly non-Asian populations. PLAIN LANGUAGE SUMMARY: Brivaracetam is used to treat partial or focal seizures in people with epilepsy. Most studies with brivaracetam tablets have involved people from non-Asian racial backgrounds. In this study, 449 Asian adults with epilepsy took part. One third took 50 mg of brivaracetam, one third took 200 mg of brivaracetam, and one third took a placebo each day for 12 weeks. On average, those who took brivaracetam had fewer seizures than those given the placebo. Most of the side effects were mild and the number and type of side effects seen were as expected for this medication.

Pharmacokinetics of Staccato® alprazolam in healthy adult participants in two phase 1 studies: An open-label smoker study and a randomized, placebo-controlled ethnobridging study.

OBJECTIVE: Staccato® alprazolam is a single-use, drug-device combination delivering alprazolam to the deep lung that is being evaluated as treatment for rapid and early seizure termination. This article reports pharmacokinetic (PK) data from two phase 1 studies of Staccato alprazolam in healthy adult participants. METHODS: The smoker study (EPK-002/NCT03516305) was an open-label, nonrandomized, single-dose, PK study in smokers and nonsmokers aged 21-50 years, administered a single inhaled dose of 1 mg Staccato alprazolam. The ethnobridging study (UP0101/NCT04782388) was a double-blind, placebo-controlled study in Japanese, Chinese, and Caucasian participants aged 18-55 years randomized 4:1 to a single inhaled dose of Staccato alprazolam 2 mg or Staccato placebo. RESULTS: In the smoker study, 36 participants (18 smokers, 18 nonsmokers) were enrolled and received Staccato alprazolam. Following Staccato administration, alprazolam was rapidly absorbed, with a median time to peak drug plasma concentration (Tmax) of 2 min in both smokers (range = 2-30 min) and nonsmokers (range = 2-60 min). Staccato alprazolam was rapidly absorbed to a similar extent in both smokers and nonsmokers. The most commonly reported treatment-emergent adverse events (TEAEs) were somnolence and dizziness. In the ethnobridging study, 10 participants each of Japanese, Chinese, and Caucasian ethnicities were randomized 4:1 to Staccato alprazolam or Staccato placebo. Following Staccato administration, alprazolam was rapidly absorbed and distributed, with a median Tmax of 1.5-2 min in Japanese (range = 1-2 min), Chinese (range = 1-34 min), and Caucasian (range = 1-120 min) participants. Somnolence and sedation were the most commonly reported TEAEs. In both studies, there were no deaths, and no participants reported serious or severe TEAEs, or discontinued due to TEAEs. SIGNIFICANCE: Alprazolam was rapidly absorbed, and therapeutic drug levels were achieved within 2 min postdose when administered to the lung with the Staccato device. Staccato alprazolam was generally well tolerated and displayed a safety profile consistent with that known from other alprazolam applications. No new safety signals were identified.

Difference in Size at Maturity in Annual and Overwintering Generations in the Tanaidacean Zeuxo sp. in Oshoro Bay, Hokkaido, Japan.

We investigated the life cycle of the tanaidid Zeuxo sp. 1 (Crustacea: Peracarida: Tanaidacea), which lives epiphytically in dwelling tubes on the algae Sargassum spp. and Neorhodomela aculeata in Oshoro Bay, Hokkaido, Japan. We obtained data on its population size distribution, age structure, and reproductive phenology through monthly sampling from April 2011 to June 2012. From these data, we detected an overwintering group (F0) that arises from mancae that are released in autumn, overwinters, reproduces the following spring, and then disappears. The overwintering group produces mancae (F1) that reach maturity and themselves reproduce within six weeks after release; the F1, mancae give rise to an F2 and possibly an F3 generation within a single summer. We refer to individuals that reproduce in the same summer that they were released as the 'annual group'. Reproduction overall was restricted to the period from May to October, when the seasurface temperature exceeded 10°C. During both years, overwintering females first became reproductive in May. Reproduction in the annual group began in June and continued through mid-October. Mancae were observed in samples from June through October. The two groups differed significantly in size at reproduction; compared to the annual group, females in the overwintering group reproduced at larger minimum and average body sizes, and males began to express enlarged chelae, a secondary sexual character, at a larger size. The difference in size at maturity may be related to the differences in water temperature during the main period of growth and maturation.

Development of a Time-Intensity Evaluation System for Consumers: Measuring Bitterness and Retronasal Aroma of Coffee Beverages in 106 Untrained Panelists.

In order to develop products that are acceptable to consumers, it is necessary to incorporate consumers' intentions into products' characteristics. Therefore, investigation of consumers' perceptions of the taste or smell of common beverages provides information that should be useful in predicting market responses. In this study, we sought to develop a time-intensity evaluation system for consumer panels. Using our system, we performed time-intensity evaluation of flavor attributes (bitterness and retronasal aroma) that consumers perceived after swallowing a coffee beverage. Additionally, we developed quantitative evaluation methods for determining whether consumer panelists can properly perform time-intensity evaluation. In every trial, we fitted an exponential function to measured intensity data for bitterness and retronasal aroma. The correlation coefficients between measured time-intensity data and the fitted exponential curves were greater than 0.8 in about 90% of trials, indicating that we had successfully developed a time-intensity system for use with consumer panelists, even after just a single training trial using a nontrained consumer. We classified participants into two groups based on their consumption of canned coffee beverages. Significant difference was observed in only AUC of sensory modality (bitterness compared with retronasal aroma) among conventional TI parameters using two-way ANOVA. However, three-way ANOVA including a time course revealed significant difference between bitterness and retronasal aroma in the high-consumption group. Moreover, the high-consumption group more easily discriminated between bitterness and retronasal aroma than the low-consumption group. This finding implied that manufacturers should select consumer panelists who are suitable for their concepts of new products.