Real-World Analysis of Clinical Characteristics, Treatment Patterns, and Patient-Reported Outcomes of Insufficient Responders and Responders to Prescribed Acute Migraine Treatment in China.

INTRODUCTION: Migraine is a common disabling primary headache disorder characterized by attacks of severe pain, sometimes accompanied by symptoms including nausea and photo-/phono-phobia. Real-world data of patients with migraine who sufficiently (responders) and insufficiently (insufficient responders) respond to acute treatment (AT) are limited in China. This analysis explored whether responders to AT differ from insufficient responders in terms of clinical characteristics, treatment patterns, and patient-reported outcomes in China. METHODS: Data were drawn from the Adelphi Migraine Disease Specific Programme™, a point-in-time survey of internists/neurologists and their consulting patients with migraine, conducted in a real-world setting in China, January-June 2014. Responders and insufficient responders to prescribed AT were patients who typically achieved headache pain freedom within 2 h of AT in ≥ 4 and ≤ 3 of five migraine attacks, respectively. Responders were compared with insufficient responders; logistic regression was used to identify factors associated with insufficient response. RESULTS: Of 777 patients currently receiving AT, 44.0% were insufficient responders. Significantly fewer responders than insufficient responders had migraine with aura (13.1 vs. 23.8%; p = 0.0001). Responders reported a significantly lower mean Migraine Disability Assessment (MIDAS) total score (5.5 vs. 6.6; p = 0.0325). Responders reported a lower mean impairment while working (50.0 vs. 63.9%; p < 0.0001), overall work impairment (52.6 vs. 66.0%; p < 0.0001), and activity impairment (48.9 vs. 59.0%; p < 0.0001). Statistically significant factors associated with insufficient response to AT included diabetes, unilateral pain, vomiting, sensitivity to smell, visual aura/sight disturbance, and an increase in MIDAS total score. However, there were no statistically significant differences in ATs received by responders and insufficient responders at any regimen of therapy. CONCLUSIONS: Many patients with migraine in China are insufficient responders to AT, experiencing worse symptoms that lead to overall poorer quality of life than responders. This unmet need suggests that new effective treatment options are required for migraine.

Real-World Treatment Patterns and Outcomes Among Patients with Episodic Migraine in China: Results from the Adelphi Migraine Disease Specific Programme™.

Objective: This study assessed treatment patterns, disease burden, outcomes, and unmet needs among patients with episodic migraine (EM) in China using Adelphi Migraine Disease Specific Programme™ (DSP) real-world data. Background: Migraine is a prevalent and debilitating neurological disorder which presents a major public health burden globally. Research on characteristics, disease burden, and treatment patterns in EM patients in China is limited. Methods: Data were drawn from an existing data set Adelphi Migraine DSP, a point-in-time survey conducted in China (January-June 2014). Internists/neurologists completed patient record forms for the next 9 patients who consulted them in clinical practice; these same patients completed the 'patient self-completion questionnaires'. Descriptive analyses were used to assess key variables: patient demographics, treatment patterns (current acute and preventive medication [AM/PM]), effectiveness, issues with existing treatment, Migraine Disability Assessment (MIDAS) scores, and Work Productivity and Activity Impairment scores. Results: Total of 125 internists/neurologists provided data on 1113 patients with EM (headache days/month <15). Mean (standard deviation [SD]) age was 43.8 (13.1) years; mean (SD) number of migraine days/month was 3.2 (1.7). AM was prescribed in 86.1% of patients (non-steroid anti-inflammatory drugs [NSAIDs]: 62.7%; triptans: 7.7%), PM in 38.5%, and both in 24.9% of patients. Approximately 55% of patients experienced ≥1 issue with their current AM or PM. Migraine-related symptoms (including nausea, photophobia, and phonophobia) were fully controlled in <50% of patients receiving NSAIDs (21.7-38.4%) or triptans (32.4-43.5%). Insufficient response to current AM (migraine headache fully resolved within 2 hours in ≤3/5 attacks) was reported by 42.5% of patients. Mild-to-severe disability was reported by 36.8% of patients with a mean (SD) MIDAS score of 5.8 (7.3). Overall, 58.0% of work time was impaired (including time missed and impairment while working). Conclusion: This analysis suggests, despite existing treatment options, disease burden and unmet medical needs remain substantial in Chinese patients with EM.

Genesis of a functional astrocyte syncytium in the developing mouse hippocampus.

Astrocytes are increasingly shown to operate as an isopotential syncytium in brain function. Protoplasmic astrocytes acquire this ability to functionally go beyond the single-cell level by evolving into a spongiform morphology, cytoplasmically connecting into a syncytium, and expressing a high density of K+ conductance. However, none of these cellular/functional features exist in neonatal newborn astrocytes, which imposes a basic question of when a functional syncytium evolves in the developing brain. Our results show that the spongiform morphology of individual astrocytes and their spatial organization all reach stationary levels by postnatal day (P) 15 in the hippocampal CA1 region. Functionally, astrocytes begin to uniformly express a mature level of passive K+ conductance by P11. We next used syncytial isopotentiality measurement to monitor the maturation of the astrocyte syncytium. In uncoupled P1 astrocytes, the substitution of endogenous K+ by a Na+ -electrode solution ([Na+ ]p ) resulted in the total elimination of the physiological membrane potential (VM ), and outward K+ conductance as predicted by the Goldman-Hodgkin-Katz (GHK) equation. As more astrocytes are coupled to each other through gap junctions during development, the [Na+ ]p -induced loss of physiological VM and the outward K+ conductance is progressively compensated by the neighboring astrocytes. By P15, a stably established syncytial isopotentiality (-73 mV), and a fully compensated outward K+ conductance appeared in all [Na+ ]p -recorded astrocytes. Thus, in view of the developmental timeframe wherein a singular syncytium is anatomically and functionally established for intra-syncytium K+ equilibration, an astrocyte syncytium becomes fully operational at P15 in the mouse hippocampus.

Safety Findings in Lasmiditan as a Novel Acute Treatment of Migraine in Chinese Patients: A Post Hoc Analysis of the Randomized Controlled Phase 3 CENTURION Trial.

INTRODUCTION: Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase 3 study of lasmiditan in Caucasian and Chinese patients with migraine. This post hoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed. METHODS: Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed. RESULTS: A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy. CONCLUSION: In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population. TRIAL REGISTRATION: NCT03670810.

Although there is significant unmet medical need among patients with migraine, there has been no novel compound for treatment of migraine over past two decades in China. These unmet medical needs persist because the current available medications for the acute treatment of migraine are reported to have safety and tolerability issues. Lasmiditan is a new class of acute migraine medication (5-HT receptor agonist with high selectivity for the 5-HT_1F receptor) with a proven efficacy and safety in phase 2 and 3 studies. Owing to some differences in clinical practice between China and western countries, there is need to get additional evidence on safety of lasmiditan in the Chinese population to support its usage in clinical practice.This post hoc analysis was conducted to present the detailed safety profile of lasmiditan in the Chinese population using data from the CENTURION study. Approximately half of the analyzed population was not covered in the published primary cohort.The results show that in the Chinese population of the study, most of the treatment-emergent adverse events (TEAEs) were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort with no new safety concerns observed in the Chinese population. The overall safety profile of lasmiditan in the Chinese population was generally consistent with the primary cohort. The results provide additional evidence and emphasize that lasmiditan may be considered as a useful acute treatment option with acceptable safety profile for patients with migraine in China.

Syncytial isopotentiality: A system-wide electrical feature of astrocytic networks in the brain.

Syncytial isopotentiality, resulting from a strong electrical coupling, emerges as a physiological mechanism that coordinates individual astrocytes to function as a highly efficient system in brain homeostasis. However, whether syncytial isopotentiality occurs selectively to certain brain regions or is universal to astrocytic networks remains unknown. Here, we have explored the correlation of syncytial isopotentiality with different astrocyte subtypes in various brain regions. Using a nonphysiological K+ -free/Na+ electrode solution to depolarize a recorded astrocyte in situ, the existence of syncytial isopotentiality can be revealed: the recorded astrocyte's membrane potential remains at a quasi-physiological level due to strong electrical coupling with neighboring astrocytes. Syncytial isopotentiality appears in Layer I of the motor, sensory, and visual cortical regions, where astrocytes are organized with comparable cell densities, interastrocytic distances, and the quantity of directly coupled neighbors. Second, though astrocytes vary in their cytoarchitecture in association with neuronal circuits from Layers I-VI, the established syncytial isopotentiality remains comparable among different layers in the visual cortex. Third, neurons and astrocytes are uniquely organized as barrels in Layer IV somatosensory cortex; interestingly, astrocytes both inside and outside of the barrels do electrically communicate with each other and also share syncytial isopotentiality. Fourth, syncytial isopotentiality appears in radial-shaped Bergmann glia and velate astrocytes in the cerebellar cortex. Fifth, although fibrous astrocytes in white matter exhibit a distinct morphology, their network syncytial isopotentiality is comparable with protoplasmic astrocytes. Altogether, syncytial isopotentiality appears as a system-wide electrical feature of astrocytic networks in the brain.

Electrophysiological behavior of neonatal astrocytes in hippocampal stratum radiatum.

BACKGROUND: Neonatal astrocytes are diverse in origin, and undergo dramatic change in gene expression, morphological differentiation and  syncytial networking throughout development. Neonatal astrocytes also play multifaceted roles in neuronal circuitry establishment. However, the extent to which neonatal astrocytes differ from their counterparts in the adult brain remains unknown. RESULTS: Based on ALDH1L1-eGFP expression or sulforhodamine 101 staining, neonatal astrocytes at postnatal day 1-3 can be reliably identified in hippocampal stratum radiatum. They exhibit a more negative resting membrane potential (V M), -85 mV, than mature astrocytes, -80 mV and a variably rectifying whole-cell current profile due to complex expression of voltage-gated outward transient K(+) (IKa), delayed rectifying K(+) (IKd) and inward K(+) (IKin) conductances. Differing from NG2 glia, depolarization-induced inward Na(+) currents (INa) could not be detected in neonatal astrocytes. A quasi-physiological V M of -69 mV was retained when inwardly rectifying Kir4.1 was inhibited by 100 µM Ba(2+) in both wild type and TWIK-1/TREK-1 double gene knockout astrocytes, indicating expression of additional leak K(+) channels yet unknown. In dual patch recording, electrical coupling was detected in 74 % (14/19 pairs) of neonatal astrocytes with largely variable coupling coefficients. The increasing gap junction coupling progressively masked the rectifying K(+) conductances to account for an increasing number of linear voltage-to-current relationship passive astrocytes (PAs). Gap junction inhibition, by 100 µM meclofenamic acid, substantially reduced membrane conductance and converted all the neonatal PAs to variably rectifying astrocytes. The low density expression of leak K(+) conductance in neonatal astrocytes corresponded  to a ~50 % less K(+) uptake capacity compared to adult astrocytes. CONCLUSIONS: Neonatal astrocytes predominantly express a variety of rectifying K(+) conductances, form discrete cell-to-cell gap junction coupling and are deficient in K(+) homeostatic capacity.

Genetic Deletion of TREK-1 or TWIK-1/TREK-1 Potassium Channels does not Alter the Basic Electrophysiological Properties of Mature Hippocampal Astrocytes In Situ.

We have recently shown that a linear current-to-voltage (I-V) relationship of membrane conductance (passive conductance) reflects the intrinsic property of K(+) channels in mature astrocytes. While passive conductance is known to underpin a highly negative and stable membrane potential (V M) essential for the basic homeostatic function of astrocytes, a complete repertoire of the involved K(+) channels remains elusive. TREK-1 two-pore domain K(+) channel (K2P) is highly expressed in astrocytes, and covalent association of TREK-1 with TWIK-1, another highly expressed astrocytic K2P, has been reported as a mechanism underlying the trafficking of heterodimer TWIK-1/TREK-1 channel to the membrane and contributing to astrocyte passive conductance. To decipher the individual contribution of TREK-1 and address whether the appearance of passive conductance is conditional to the co-expression of TWIK-1/TREK-1 in astrocytes, TREK-1 single and TWIK-1/TREK-1 double gene knockout mice were used in the present study. The relative quantity of mRNA encoding other astrocyte K(+) channels, such as Kir4.1, Kir5.1, and TREK-2, was not altered in these gene knockout mice. Whole-cell recording from hippocampal astrocytes in situ revealed no detectable changes in astrocyte passive conductance, V M, or membrane input resistance (R in) in either kind of gene knockout mouse. Additionally, TREK-1 proteins were mainly located in the intracellular compartments of the hippocampus. Altogether, genetic deletion of TREK-1 alone or together with TWIK-1 produced no obvious alteration in the basic electrophysiological properties of hippocampal astrocytes. Thus, future research focusing on other K(+) channels may shed light on this long-standing and important question in astrocyte physiology.

Low-dose levodopa protects nerve cells from oxidative stress and up-regulates expression of pCREB and CD39.

OBJECTIVE: This study aimed to investigate the influence of low-dose levodopa (L-DOPA) on neuronal cell death under oxidative stress. METHODS: PC12 cells were treated with L-DOPA at different concentrations. We detected the L-DOPA induced reactive oxygen species (ROS). Meanwhile, MTT and LDH assay were performed to determine the proliferation and growth of PC12 cells with or without ROS scavenger. In addition, after pretreatment with L-DOPA at different concentrations alone or in combination with CD39 inhibitor, PC12 cells were incubated with hydrogen peroxide (H2O2) and the cell viability was evaluated by MTT and LDH assay. In addition, the expression of pCREB and CD39 was detected by immunofluorescence staining and Western blot assay in both cells and rat's brain after L-DOPA treatment. RESULTS: After treatment with L-DOPA for 3 days, the cell proliferation and growth were promoted when the L-DOPA concentration was <30 µM, while cell proliferation was comparable to that in control group when the L-DOPA concentration was >30 µM. Low dose L-DOPA could protect the PC12 cells from H2O2 induced oxidative stress, which was compromised by CD39 inhibitor. In addition, the expression of CD39 and pCREB increased in both PC12 cells and rats' brain after L-DOPA treatment. CONCLUSIONS: L-DOPA at different concentrations has distinct influence on proliferation and growth of PC12 cells, and low dose (<30 µM) L-DOPA protects PC12 cells against oxidative stress which might be related to the up-regulation of CD39 and pCREB expression.