Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Reduced Sleep Quality Is Related to Poor Quality of Life in Patients with Juvenile Myoclonic Epilepsy, a Case-Control Study.

Juvenile myoclonic epilepsy (JME) is a primary generalized epilepsy which is closely related to the sleep-wake cycle. This study aimed to investigate whether sleep disturbance is more common among patients with JME and the impact this may have on their quality of life (QOL). Thirty-four patients with JME and age- and gender-matched controls were recruited into this case control study, and assessed using validated sleep questionnaires including the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Stanford Sleepiness Scale (SSS). QOL was assessed using the Quality of Life in Epilepsy Inventory (QOLIE-31). The patients had a significantly higher PSQI score and higher proportion of abnormal PSQI scores than the controls. They also had higher ESS and SSS scores, but without statistical significance. The patients with poor sleep quality had significantly lower overall QOL, emotional well-being, and energy/fatigue subscale scores. The use of a higher number of antiseizure medications, dosage of levetiracetam, and usage of antiseizure medication polytherapy were associated with sleep disorders. Our results showed that sleep disturbance is common in patients with JME, and also that it has an impact on their QOL.

Aggressive cytoreduction and multiple subpial cortical transections may obtain good surgical outcomes in refractory epilepsy with multiple epileptic foci.

BACKGROUNDS: Epilepsy surgery is the most efficacious therapeutic modality for patients with medical refractory epilepsy, especially resective surgery. However, the variable etiologies and multiple epileptic foci are usually associated with the outcomes. The aim of this study was to demonstrate that combination of different intervention procedures might be an alternative option for patients of refractory epilepsy. METHODS: We retrospectively analyzed pre-operative and post-surgical outcomes in 30 patients who received epilepsy surgery between January 1, 2010 and December 31, 2014 at Chang Gung Memorial Hospital (CGMH), Linkou, according to Engel's classification. RESULTS: Twenty-six of the 30 patients (86.7%) had good outcomes, sum of class I and class II after epilepsy surgery. The good outcome rate of our complicated group was 80.0% (12/15), compared to 93.3% (14/15) in the simple group, but no significant differences between the two groups (p = 0.569). Four patients whose epileptic foci involved eloquent area and received multiple subpial cortical transection, and good outcome rate was 75% (3/4). At last, six patients had previously failed epilepsy surgery and received a reoperation, with a good outcome rate of 83.3% (5/6). CONCLUSION: After complete pre-surgical evaluation and combined interventional procedures, the patients with refractory epilepsy had satisfactory outcomes and few neurological complications. Moreover, re-operation can improve the outcome in some patients who previously failed epilepsy surgery.

Potential Role of Nrf2 Activators with Dual Antiviral and Anti-Inflammatory Properties in the Management of Viral Pneumonia.

The outbreak of coronavirus disease 2019 (COVID-19) pandemic has already caused a huge burden to the global healthcare system, with the death toll reached tens of thousands. Although some antiviral agents were identified and used to inhibit viral replication, the management of cytokine storm is also a critical issue. In this article, we reviewed the literature on drug candidates for severe acute respiratory syndrome (SARS-CoV-1) and provided a brief overview of a class of drugs that exert antiviral and anti-inflammatory effects. These molecules mitigated inflammatory cytokine cascades induced by viral infections via Nrf2 activating capacity and might have additional anti-fibrotic and anti-remodeling properties. Besides, their effects on the regulation of scavenger receptors expression by macrophages may offer some benefits to the pulmonary antibacterial defense system after viral infection. The potential roles of these agents assessed on the basis of the pathophysiology of viral pneumonia and acute respiratory distress syndrome were also discussed. Further research is needed to ascertain whether Nrf2 activators are useful in the management of viral pneumonia.

Effectiveness and safety of perampanel in adults with mesial temporal epilepsy: A single-center postmarketing study in Taiwan.

Mesial temporal lobe epilepsy (MTLE) is a common epilepsy syndrome often refractory to antiepileptic drug (AED) treatment. The purpose of this study was to evaluate the effectiveness and tolerability of perampanel (PER) as add-on treatment for patients of MTLE.We pooled retrospective data from adult patients with MTLE, from a tertiary center in Taiwan, who were prescribed PER between March 2016 and December 2016. The retention, responder, and seizure-free rate as well as the treatment emergent adverse events were assessed after 6 months of PER adjunctive treatment in this single-center postmarketing study.Review of medical records revealed that adequate data were available for 44 patients who were being administered PER (mean age: 42.0 ±â€Š13.3 years, 24 females; baseline mean seizure frequency: 5.4 per 28 days). Twelve patients exhibited hippocampal sclerosis (HS). Open-label PER was added to ongoing medications. Twelve patients withdrew because of ineffectiveness (n = 6) or adverse effects (n = 6). The retention rate was 72.7% at 6 months. On final evaluation, with a mean PER dose of 5.7 mg/day for 6 months, a ≥50% reduction in seizure frequency was observed in 46.9% of the patients, and 5 patients became seizure-free. The effectiveness was similar for patients with or without HS. Twenty-three patients (52.3%) experienced adverse effects. The most common adverse effects were dizziness, ataxia, and irritability.Our results suggest that PER, at doses of 2 to 12 mg/day, reduces seizure frequency effectively with acceptable safety profiles for adults with MTLE.

Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study.

BACKGROUND: The incidence of cefepime-induced neurotoxicity (CIN) has been previously underestimated, and there have only been sporadic reports from critical neurological settings. The present study aimed to investigate the potential factors associated with disease development, electroencephalography (EEG) sub-classification, and outcome measures. METHODS: The 10-year medical records of patients who underwent EEG between 2007 and 2016 at a tertiary medical center in Taiwan, and developed encephalopathy after cefepime therapy were retrospectively reviewed. Age- and sex-matched controls were included for further analysis. Demographic data, the occurrence of clinical seizures, non-convulsive status epilepticus (NCSE), use of antiepileptic drugs (AEDs), receiving maintenance or urgent hemodialysis, EEG findings, and functional outcomes were analyzed. The Chi-square test and a logistic regression model were applied to survey significant prognostic factors relating to mortality. RESULTS: A total of 42 CIN patients were identified, including 25 patients from wards and 17 from intensive care units; their mean age was 75.8 ± 11.8 years. Twenty-one patients (50%) had chronic kidney disease, and 18 (43%) had acute kidney injury. Among these patients, 32 (76%) received appropriate cefepime dose adjustment. Three patients had a normal renal function at the time of CIN onset. The logistic regression model suggested that maintenance hemodialysis and longer duration of cefepime use were independently associated with the development of CIN, with odds ratios of 3.8 and 1.2, respectively. NCSE was frequently noted in the CIN patients (64%). Generalized periodic discharge with or without triphasic morphology was the most common EEG pattern (38%), followed by generalized rhythmic delta activity and generalized spike-and-waves. AEDs were administered to 86% of the patients. A total of 17 patients (40%) did not survive to hospital discharge. Adequate cefepime dose adjustment and early cefepime discontinuation led to a better prognosis. CONCLUSIONS: CIN was associated with high mortality and morbidity rates. Neurotoxic symptoms could still occur when the cefepime dose was adjusted, or in patients with normal renal function. Patients with maintenance hemodialysis or a longer duration of cefepime therapy tended to develop CIN. Early recognition of abnormal EEG findings allowed for the withdrawal of the offending agent, resulting in clinical improvements and a better prognosis at discharge.

CK2-mediated stimulation of Pol I transcription by stabilization of UBF-SL1 interaction.

High levels of rRNA synthesis by RNA polymerase I are important for cell growth and proliferation. In vitro studies have indicated that the formation of a stable complex between the HMG box factor [Upstream binding factor (UBF)] and SL1 at the rRNA gene promoter is necessary to direct multiple rounds of Pol I transcription initiation. The recruitment of SL1 to the promoter occurs through protein interactions with UBF and is regulated by phosphorylation of UBF. Here we show that the protein kinase CK2 co-immunoprecipitates with the Pol I complex and is associated with the rRNA gene promoter. Inhibition of CK2 kinase activity reduces Pol I transcription in cultured cells and in vitro. Significantly, CK2 regulates the interaction between UBF and SL1 by counteracting the inhibitory effect of HMG boxes five and six through the phosphorylation of specific serines located at the C-terminus of UBF. Transcription reactions with immobilized templates indicate that phosphorylation of CK2 phosphoacceptor sites in the C-terminal domain of UBF is important for promoting multiple rounds of Pol I transcription. These data demonstrate that CK2 is recruited to the rRNA gene promoter and directly regulates Pol I transcription re-initiation by stabilizing the association between UBF and SL1.

Direct regulation of rRNA transcription by fibroblast growth factor 2.

Fibroblast growth factor 2 (FGF-2), which is highly expressed in developing tissues and malignant cells, regulates cell growth, differentiation, and migration. Five isoforms (18 to approximately 34 kDa) of FGF-2 are derived from alternative initiation codons of a single mRNA. The 18-kDa FGF-2 isoform is released from cells by a nonclassical secretory pathway and regulates gene expression by binding to cell surface receptors. This isoform also localizes to the nucleolus, raising the possibility that it may directly regulate ribosome biogenesis, a rate-limiting process in cell growth. Although several growth factors have been shown to accumulate in the nucleolus, their function and mechanism of action remain unclear. Here we show that 18-kDa FGF-2 interacts with upstream binding factor (UBF), an architectural transcription factor essential for rRNA transcription. The maximal activation of rRNA transcription in vitro by 18-kDa FGF-2 requires UBF. The 18-kDa FGF-2 localizes to rRNA genes and is necessary for the full activation of pre-rRNA synthesis in vivo. Our results demonstrate that 18-kDa FGF-2 directly regulates rRNA transcription.

Improvement of glycosylation in insect cells with mammalian glycosyltransferases.

The N-glycans of recombinant glycoproteins expressed in insect cells mainly contain high mannose or tri-mannose structures, which are truncated forms of the sialylated N-glycans found in mammalian cells. Because asialylated glycoproteins have a shorter half-life in blood circulation, we investigated if sialylated therapeutic glycoprotein can be produced from insect cells by enhancing the N-glycosylation machinery of the cells. We co-expressed in two insect cell lines, Sf9 and Ea4, the human alpha1-antitrypsin (halpha1AT) protein with a series of key glycosyltransferases, including GlcNAc transferase II (GnT2), beta1,4-galactosyltransferase (beta14GT), and alpha2,6-sialyltransferase (alpha26ST) by a single recombinant baculovirus. We demonstrated that the enhancement of N-glycosylation is cell type-dependent and is more efficient in Ea4 than Sf9 cells. Glycan analysis indicated that sialylated halpha1AT proteins were produced in Ea4 insect cells expressing the above-mentioned exogenous glycosyltransferases. Therefore, our expression strategy may simplify the production of humanized therapeutic glycoproteins by improving the N-glycosylation pathway in specific insect cells, with an ensemble of exogenous glycosyltransferases in a single recombinant baculovirus.

The cell cycle regulatory factor TAF1 stimulates ribosomal DNA transcription by binding to the activator UBF.

Control of ribosome biogenesis is a potential mechanism for the regulation of cell size during growth, and a key step in regulating ribosome production is ribosomal RNA synthesis by RNA polymerase I (Pol I). In humans, Pol I transcription requires the upstream binding factor UBF and the selectivity factor SL1 to assemble coordinately on the promoter. UBF is an HMG box-containing factor that binds to the rDNA promoter and activates Pol I transcription through its acidic carboxy-terminal tail. Using UBF (284-670) as bait in a yeast two-hybrid screen, we have identified an interaction between UBF and TAF1, a factor involved in the transcription of cell cycle and growth regulatory genes. Coimmunoprecipitation and protein-protein interaction assays confirmed that TAF1 binds to UBF. Confocal microscopy showed that TAF1 colocalizes with UBF in Hela cells, and cell fractionation experiments provided further evidence that a portion of TAF1 is localized in the nucleolus, the organelle devoted to ribosomal DNA transcription. Cotransfection and in vitro transcription assays showed that TAF1 stimulates Pol I transcription in a dosage-dependent manner. Thus, TAF1 may be involved in the coordinate expression of Pol I- and Pol II-transcribed genes required for protein biosynthesis and cell cycle progression.