Bioavailability and bioequivalence comparison of brivaracetam 10, 50, 75, and 100 mg tablets and 100 mg intravenous bolus
To determine the bioequivalence of brivaracetam oral tablet formulations (10, 75, and 100 mg) versus 50 mg oral tablet and to compare the bioavailability of brivaracetam 100 mg intravenous (i.v.) bolus versus 50 and 100 mg tablets, in healthy participants.Methods
Phase 1, randomized, open-label, five-period crossover study. Participants received five single doses of brivaracetam: 10, 50 (reference), 75, and 100 mg oral tablets; 100 mg, i.v., bolus injection. Pharmacokinetic parameters (maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [AUCt], area under the plasma concentration-time curve extrapolated to infinity [AUCinf]) were compared using analysis of variance (ANOVA) following dose normalization and logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares mean ratios (test: reference).Results
Twenty-five participants were randomized. The 90% CIs around Cmax, AUCt, and AUCinf ratios for brivaracetam 10, 75, and 100 mg tablets versus 50 mg tablet were entirely contained within the bioequivalence limits (0.8000–1.2500). For brivaracetam 100 mg, i.v., bolus, bioequivalence versus 50 and 100 mg tablets was met for AUCt and AUCinf, but Cmax was partly outside the limits (90% CI: 1.1867–1.3863 and 1.1222–1.3136, respectively).Significance
Brivaracetam 10, 75, and 100 mg tablets were bioequivalent to the 50 mg tablet. Brivaracetam 100 mg, i.v., bolus had bioavailability similar to that of 50 and 100 mg tablets.
Vigabatrin is a highly effective antiseizure medication, but its use is limited due to concerns about retinal toxicity. One proposed mechanism for this toxicity is vigabatrin-mediated reduction of taurine. Herein we assess plasma taurine levels in a retrospective cohort of children with epilepsy, including a subset receiving vigabatrin. All children who underwent a plasma amino acid analysis as part of their clinical evaluation between 2006 and 2015 at Stanford Children's Health were included in the analysis. There were no significant differences in plasma taurine levels between children taking vigabatrin (n = 16), children taking other anti-seizure medications, and children not taking any anti-seizure medication (n = 556) (analysis of variance [ANOVA] p = 0.841). There were, however, age-dependent decreases in plasma taurine levels. Multiple linear regression revealed no significant association between vigabatrin use and plasma taurine level (p = 0.87) when controlling for age. These results suggest that children taking vigabatrin maintain normal plasma taurine levels, although they leave unanswered whether taurine supplementation is necessary or sufficient to prevent vigabatrin-associated visual field loss. They also indicate that age should be taken into consideration when evaluating taurine levels in young children.
Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment
To analyze seizure-like motor phenomena immediately occurring after concussion (concussive convulsions).Methods
Twenty-five videos of concussive convulsions were obtained from YouTube as a result of numerous sports-related search terms. The videos were analyzed by four independent observers, documenting observations of the casualty, the head injury, motor symptoms of the concussive convulsions, the postictal period, and the outcome.Results
Immediate responses included the fencing response, bear hug position, and bilateral leg extension. Fencing response was the most common. The side of the hit (p = 0.039) and the head turning (p = 0.0002) was ipsilateral to the extended arm. There was a tendency that if the blow had only a vertical component, the bear hug position appeared more frequently (p = 0.12). The motor symptom that appeared with latency of 6 ± 3 s was clonus, sometimes superimposed with tonic motor phenomena. Clonus was focal, focally evolving bilateral or bilateral, with a duration of 27 ± 19 s (5–72 s). Where lateralization of clonus could be determined, the side of clonus and the side of hit were contralateral (p = 0.039).Significance
Concussive convulsions consist of two phases. The short-latency first phase encompasses motor phenomena resembling neonatal reflexes and may be of brainstem origin. The long-latency second phase consists of clonus. We hypothesize that the motor symptoms of the long-latency phase are attributed to cortical structures; however, they are probably not epileptic in origin but rather a result of a transient cortical neuronal disturbance induced by mechanical forces.
This study attempted to validate the effects of neonatal estradiol in ameliorating the spasms in the prenatally betamethasone-primed N-methyl-d-aspartate (NMDA) model of infantile spasms in rats as shown previously in a mouse Arx gene knock-in expansion model of infantile spasms.Methods
Neonatal rats prenatally exposed to betamethasone (on day 15 of pregnancy) were treated with subcutaneous 40 ng/g estradiol benzoate (EB) between postnatal days (P)3–P10 or P0–P5. A synthetic estrogen analogue, diethylstilbestrol, was used between P0 and P5 (2 μg per rat, s.c.). On P12, P13, and P15, the rats were subjected to NMDA-triggered spasms, and latency to onset and number of spasms were evaluated. Rats with EB on P3–P10 were tested after spasms in the open field, novel object recognition, and elevated plus maze to determine effects of treatment on behavior. Additional rats with P3–P10 or P0–P5 EB were investigated for γ-aminobutyric acid (GABA)ergic neurons (glutamate decarboxylase [GAD]67 expression) in the neocortex. As a positive control, a group of rats received either subcutaneous adrenocorticotropic hormone (ACTH) (2 × 0.3 mg/kg on P12 and 3 × 0.3 mg/kg on P13 and P14) or vehicle after the first episode of spasms on P12.Results
Neither EB treatment nor diethylstilbestrol consistently affected expression of spasms in this model, although we found a significant increase in GAD67-immunopositive cells in the neocortex after P3–P10 and P0–P5 EB treatment, consistent with a study in mice. Behavioral tests showed increase in lateralization in male rats treated with P3–P10 EB, a behavioral trait usually associated with female sex. Diethylstilbestrol treatment in male rats resulted in arrested pubertal descent of testes. ACTH had robust effects in suppressing spasms.Significance
Treatment of infantile spasms (IS) using neonatal EB may be justified in those cases of IS that present with detectable deficits in GABAergic neurons. In other types of IS, the efficacy of neonatal EB and its analogues is not supported.
Long-term socioeconomic consequences and health care costs of childhood and adolescent-onset epilepsy
To estimate long-term socioeconomic consequences and health care costs of epilepsy with onset in childhood and adolescence.Methods
A historical prospective cohort study of Danish individuals with epilepsy, age up to 20 years at time of diagnosis between January 1981 and December 2012. Information about marital status, parenthood, educational level, employment status, income, use of the health care system, and cost of medicine was obtained from nationwide administrative and health registers.Results
We identified 12,756 and 28,319 people with diagnosed with epilepsy, ages 0–5 and 6–20 years at onset, respectively. Using follow-up data for a maximum of 30 years, 1,394 of those ages 0–5 years at onset were compared with 2,897 controls persons without epilepsy, and 10,195 of those ages 6–20 years at onset were compared with 20,678 controls without epilepsy. Compared with people without the epilepsy, those with epilepsy tended to have a lower level of education, to be less likely to be married, to be more likely to live alone, and to have higher divorce and unemployment rates, lower employment rates, and people with epilepsy were more likely to receive disability pension and social security. Income was lower from employment, which in part was compensated by social security, sick pay, disability pension and unemployment benefit, sick pay (public-funded), disability pension, and other public transfers. Predicted health care costs 30 years after epilepsy onset were significantly higher among persons with epilepsy onset at 0–5 and 6–20 years, including costs for outpatient and inpatient services (hospital services), emergency room use, primary health care sector (general practice), and use of medication.Significance
The long-term negative effects on all aspects of health care and social domains, including marital status, parental socioeconomic status, educational level, employment status, and use of welfare benefits compared with controls without epilepsy calls for increased awareness on childhood- and adolescent-onset epilepsy.