Eptinezumab for the preventive treatment of episodic and chronic migraine: a narrative review.

Eptinezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), was recently approved in Europe for the prophylactic treatment of migraine in adults who have at least four migraine days a month. Eptinezumab is administered by intravenous infusion every 12 weeks. During recent months, a considerable amount of evidence from eptinezumab trials has been published. The aim of this review is to describe the existing evidence on the tolerability, safety and efficacy of eptinezumab in patients with migraine. Data from randomized (PROMISE-1, PROMISE-2, RELIEF and DELIVER) and open-label (PREVAIL) phase 3 clinical trials have demonstrated the favorable effect of eptinezumab in migraine symptoms from first day of treatment. These studies showed that eptinezumab results in an overall reduction in mean monthly migraine days (MMDs), increases in the ≥50% and ≥ 75% migraine responder rates (MRRs) and improvements in patient-reported outcome measures in both patients with episodic migraine (EM) and with chronic migraine (CM), including patients who failed previous preventive treatments. The RELIEF trial also showed that eptinezumab, within 2 h of administration, reduced headache pain, migraine-associated symptoms and acute medication use when administered during a migraine attack. Eptinezumab benefits manifested as early as day 1 after dosing and with the subsequent doses lasted up to at least 2 years. Treatment-emergent adverse events reported by ≥2% of patients included upper respiratory tract infection and fatigue. Current evidence demonstrates that eptinezumab has a potent, fast-acting, sustained migraine preventive effect in patients with EM and CM. Eptinezumab has also shown to be well tolerated, supporting its use in the treatment of patients with migraine and inclusion in the current migraine therapeutic options.

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.

The Combined Effects of Sublingual Immunotherapy and Lactobacillus acidophilus-Producing Extract on Cedar Pollinosis Symptoms.

INTRODUCTION: Sublingual immunotherapy (SLIT), in which standardized cedar pollen extract solution is administered, has been used to treat cedar pollinosis, but SLIT is problematic because it takes a long time to become effective, and some cases are ineffective even after long-term treatment. It has also been reported that lactobacillus acidophilus extract (LEX), a food-derived ingredient, alleviates various allergic symptoms. This study examined the usefulness of LEX as a treatment for cedar pollinosis in comparison with SLIT. We also examined whether the combined use of SLIT and LEX could have an early-onset of therapeutic effect on cedar pollinosis. We also examined the usefulness of LEX as a salvage therapy for patients who failed to respond to SLIT. SUBJECTS AND METHODS: Fifteen patients with cedar pollinosis were divided into three groups. The three groups were: three patients in the standardized cedar pollen extract group (S group), seven patients in the lactobacillus-producing extract group (L group), and five patients in the combination group of standardized cedar pollen extract and lactobacillus-producing extract (SL group). The subjects were treated for three years, corresponding to the three scattering seasons of cedar pollen, and observed according to the evaluation items. The evaluation items were severity score based on examination findings, subjective symptom score (QOL score) based on the Japanese Standard QOL Questionnaire for Allergic Rhinitis (JRQLQ No. 1) questionnaire, nonspecific IgE level measurement by blood test, and cedar pollen-specific IgE level measurement. RESULTS: After three years of observation, there were no significant differences in severity score and nonspecific IgE levels among the three groups, while QOL score decreased significantly between the first and third years of treatment in the L group. Cedar pollen-specific IgE levels in the S and SL groups showed an increase in the first year and a gradual decrease in the second and third years of treatment compared to the pre-treatment period. In group L, no increase was observed in the first year, and a significant decrease was observed in the second and third years during the cedar pollen dispersal period. CONCLUSIONS: The results of severity and quality of life scores indicated that it took three years of treatment for the S and SL groups to show efficacy, while the L group showed improvement in quality of life scores and cedar pollen-specific IgE levels from the first year, suggesting that LEX is useful as a treatment for cedar pollinosis. The efficacy of combination therapy with SLIT and LEX was not clear, but since the effect of LEX was observed from the early stage of treatment, it was thought that the combination therapy with LEX intake from the early stage of treatment may be effective in reducing the incidence of ineffective cases. The combination therapy of SLIT and LEX may also be useful as a salvage therapy.

Sigma-1 receptor agonist properties that mediate the fast-onset antidepressant effect of hypidone hydrochloride (YL-0919).

The most intriguing characteristic of the sigma-1 receptor is its ability to regulate multiple functional proteins directly via protein-protein interactions, giving the sigma-1 receptor the powerful ability to regulate several survival and metabolic functions in cells, fine tune neuronal excitability, and regulate the transmission of information within brain circuits. This characteristic makes sigma-1 receptors attractive candidates for the development of new drugs. Hypidone hydrochloride (YL-0919), a novel structured antidepressant candidate developed in our laboratory, possess a selective sigma-1 receptor agonist profile, as evidenced by molecular docking, radioligand receptor binding assays, and receptor functional experiments. In vivo studies have revealed that YL-0919 elicits a fast-onset antidepressant activity (within one week) that can be attenuated with pretreatment of the selective sigma-1 receptor antagonist, BD-1047. Taken together, the findings of the current study suggest that YL-0919 activates the sigma-1 receptor to partially mediate the rapid onset antidepressant effects of YL-0919. Thus, YL-0919 is a promising candidate as a fast-onset antidepressant that targets the sigma-1 receptor.

Translocator protein-mediated fast-onset antidepressant-like and memory-enhancing effects in chronically stressed mice.

BACKGROUND: Fast-acting and cognitive-enhancing antidepressants are desperately needed. Activation of translocator protein (18 kDa, TSPO) is a novel strategy for developing potential antidepressants, but there are no data available on the onset time of TSPO ligands. This study aimed to investigate the fast-onset antidepressant actions of AC-5216, a selective TSPO ligand, in TSPO knock-out (KO) mice. METHODS: TSPO wild-type (WT) and KO mice were subjected to a six-week chronic unpredicted stress (CUS) paradigm. Then, the mice were treated with AC-5216 and tested with depressive and cognitive behaviours. RESULTS: A single dose of AC-5216 (0.3 mg/kg) exerted anxiolytic- and antidepressant-like actions in TSPO WT mice. Moreover, in chronically stressed WT mice, two to four days of AC-5216 treatment (0.3 mg/kg, once per day) produced fast-onset antidepressant-like effects in the novelty-suppressed feeding and sucrose preference tests, as well as memory-enhancing effects in the novel object recognition test. In addition, a rapid (with five days of treatment) restoration of serum corticosterone levels and prefrontal cortex (PFC) allopregnanolone levels was found. Further studies showed that in these stress-exposed WT mice, AC-5216 significantly increased the levels of mTOR signalling-related proteins (mBDNF, p-mTOR, PSD-95, synapsin-1, GluR1), as well as the total dendritic length and branching points of pyramidal neurons in the PFC. CONCLUSIONS: These results suggest that TSPO mediates the fast-onset antidepressant-like and memory-enhancing effects of AC-5216, possibly through the rapid activation of mTOR signalling and restoration of dendritic complexity in the PFC.

A hypothesis of monoamine (5-HT) - Glutamate/GABA long neural circuit: Aiming for fast-onset antidepressant discovery.

Major depressive disorder has become a global public health problem of serious concern. Most of the clinical antidepressants are developed under the classic "monoamine hypothesis (strategy)". These drugs generally have such deficiencies including slow onset and limited efficiency, cognitive impairment and suicidal tendency. Therefore, it is the direction to break through the classic monoamine strategy framework for developing antidepressants that have fast-acting, lower side effects, and cognitive enhancement, to satisfy the major clinical needs. In 2019, the launch of fast-acting antidepressants such as S-ketamine(S-Ket) and brexanolone into market by FDA has opened up new prospects for non-monoamine strategy mainly based on the N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid type A (GABAA) receptors. There are two main trends in the development of fast-onset antidepressants: the optimized multi-target monoamine strategy (modern monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance modulation. Based to the research conducted by foreign peers and our lab, we propose a hypothesis of "monoamine (5-HT)- Glu/GABA long neural circuit", which holds the view that both monoaminergic mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoaminergic mechanisms (Glu/GABA neurons located in prefrontal cortex) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long neural circuit mediating the fast synaptogenesis of the brain regions including prefrontal cortex. Based on this, it is proposed that fast launch and activation of this circuit may be an important mechanism for fast-onset of antidepressant, in which Glu/GABA (excitation/ inhibition, E/I) rebalance should be the critical rate-limiting step for the onset speed. Therefore, five potential strategies are proposed for fast-acting antidepressant based on this circuit: 1) Achieve the rapid E/I balance by relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating pyramidal neurons; 2) Simultaneously modulate 5-HT neuronal activity and Glu/GABA balance by 5-HT transporter combining with some receptors such as 5-HT1A/1B (namely simultaneous enhancement of the 5-HT and Glu/GABA links); 3) Directly activate mammalian rapamycin target protein complex 1 (mTORC1) and rapidly enhance brain-derived neurotrophic factor (BDNF) -mTOR pathway; 4) Stimulate rapid release of BDNF in the brain; 5) Positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. It is hoped that these ideas will provide possible strategies for the further development of a new generation of antidepressants and provide a useful reference for the further discovery of fast-onset antidepressant candidate targets.

Rapid Anxiolytic Effects of RS67333, a Serotonin Type 4 Receptor Agonist, and Diazepam, a Benzodiazepine, Are Mediated by Projections From the Prefrontal Cortex to the Dorsal Raphe Nucleus.

BACKGROUND: Activation of serotonin (5-HT) type 4 receptors (5-HT4Rs) has been shown to have anxiolytic effects in a variety of animal models. Characterizing the circuits responsible for these effects should offer insights into new approaches to treat anxiety. METHODS: We evaluated whether acute 5-HT4R activation in glutamatergic axon terminals arising from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN) induced fast anxiolytic effects. Anxiolytic effects of an acute systemic administration (1.5 mg/kg, intraperitoneally) or intra-mPFC infusion with the 5-HT4R agonist, RS67333 (0.5 µg/side), were examined in mice. To provide evidence that anxiolytic effects of RS67333 recruited an mPFC-DRN neural circuit, in vivo recordings of firing rate of DRN 5-HT neurons, cerebral 5-HT depletion, and optogenetic activation and silencing were performed. RESULTS: Acute systemic administration and intra-mPFC infusion of RS67333 produced fast anxiolytic effects and increased DRN 5-HT cell firing. Serotonin depletion prevented anxiolytic effects induced by mPFC infusion of RS67333. Surprisingly the anxiolytic effects of mPFC infusion diazepam (1.5 µg/side) were also blocked by 5-HT depletion. Optogenetically activating mPFC terminals targeting the DRN reduced anxiety, whereas silencing this circuit blocked RS67333 and diazepam mPFC infusion-induced anxiolytic effects. Finally, anxiolytic effects induced by an acute systemic RS67333 or diazepam administration were partially blocked after optogenetically inhibiting cortical glutamatergic terminals in the DRN. CONCLUSIONS: Our findings suggest that activating 5-HT4R acutely in the mPFC or targeting mPFC pyramidal cell terminals in the DRN might constitute a strategy to produce a fast anxiolytic response.

High-frequency oscillations and focal seizures in epileptic rodents.

High-pass filtering (> 80 Hz) of EEG signals has enabled neuroscientists to analyze high-frequency oscillations (HFOs; i.e., ripples: 80-200 Hz and fast ripples: 250-500 Hz) in epileptic patients presenting with focal seizures and in animal models mimicking this condition. Evidence obtained from these studies indicate that HFOs mirror pathological network activity that may initiate and sustain ictogenesis and epileptogenesis. HFOs are observed in temporal lobe regions of epileptic animals during interictal periods but they also occur before seizure onset and during the ictal period, suggesting that they can pinpoint to the mechanisms of seizure generation. Accordingly, ripples and fast ripples predominate during two specific seizure onset patterns termed low-voltage fast and hypersynchronous, respectively. In this review we will: (i) summarize these experimental studies; (ii) consider the evolution of HFOs over time during epileptogenesis; (iii) address data obtained with optogenetic stimulating procedures both in vitro and in vivo, and (iv) take into account the impact of anti-epileptic drugs on HFOs. We expect these findings to contribute to understanding the neuronal mechanisms leading to ictogenesis and epileptogenesis thus leading to the development of mechanistically targeted anti-epileptic strategies.

Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure.

Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast-onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast-onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL-0919 may be a powerful/effective antidepressant with fast-onset.

Discovery of DSP-1053, a novel benzylpiperidine derivative with potent serotonin transporter inhibitory activity and partial 5-HT1A receptor agonistic activity.

We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT1A partial agonistic activity, may act under high serotonin levels as a 5-HT1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one. This optimization work led to the identification of the antidepressant candidate DSP-1053 as a potent SERT inhibitor with partial 5-HT1A receptor agonistic activity. DSP-1053 showed low CYP2D6 metabolic contribution and a robust increase in serotonin levels in the rat frontal cortex.

Electrospun Hydrophilic Janus Nanocomposites for the Rapid Onset of Therapeutic Action of Helicid.

The oral delivery of active ingredients for the fast onset of therapeutic effects is a well-known method in patients. In this study, a new kind of hydrophilic Janus structural nanocomposite was designed for the rapid dissolution and transmembrane permeation of helicid, an herbal medicine with poor water solubility. A side-by-side electrospinning process characterized by an eccentric spinneret was developed to fabricate the Janus nanocomposites. The morphology, inner structure, incorporated components and their physical states, hydrophilicity, and functional performances of the Janus nanocomposites were investigated. The experimental results demonstrated that an unspinnable fluid (polyvinylpyrrolidone K10-sodium dodecyl sulfate) could be simultaneously treated with an electrospinnable fluid (polyvinylpyrrolidone K90-helicid) to create Janus structural nanocomposites. The prepared Janus nanofibers exhibited linear morphology and notable side-by-side inner structure with all the incorporated components present in an amorphous state. Both the control of monolithic nanocomposites and the Janus composites can provide more than 10-fold the transmembrane rates of crude helicid particles. Compared with monolithic nanocomposites, the Janus nanocomposites exhibited improved hydrophilicity and can further promote the dissolution and transmembrane permeation of helicid for a potentially faster onset of therapeutic actions. The generation mechanisms and functional performance of Janus nanocomposites were suggested. The preparation protocols reported here can provide a useful approach for designing and developing new functional nanocomposites in the form of Janus structures. Meanwhile, the medicated hydrophilic Janus nanocomposites represent a newly developed kind of nano drug delivery system for the fast onset of therapeutic action of orally administered water-insoluble drugs.

Corticosteroid plus ß2-agonist in a single inhaler as reliever therapy in intermittent and mild asthma: a proof-of-concept systematic review and meta-analysis.

BACKGROUND: Current guidelines recommend a single inhaler maintenance and reliever therapy (SMART) regimen for moderate to severe asthma. However, evidence for the inhaled corticosteroid plus fast-onset-acting ß2-agonist (ICS/FABA) as reliever therapy in management of intermittent and mild asthma patients is lacking. OBJECTIVE: To systematically explore efficacy and safety of the proof-of-concept of the ICS plus FABA regimen in a single inhaler as reliever therapy across children and adults with intermittent and mild persistent asthma. METHODS: We searched online bibliographic databases for randomized controlled trials (RCTs) involving the as-needed use of ICS/FABA as monotherapy in intermittent or mild asthma patients. The primary outcomes were exacerbations and the hazard ratio (HR) of the time to first exacerbation. RESULTS: Six RCTs (n = 1300) met the inclusion criteria. Compared with the as-needed FABA regimen, the as-needed use of ICS/FABA as monotherapy statistically reduced exacerbations (RR = 0.56, P = 0.001). Compared with regular ICS regimen, the as-needed ICS/FABA therapy had slightly higher risk of exacerbations (RR = 1.39, P = 0.011). The HR for time to first exacerbations in the ICS/FABA regimen was significant lower when compared with FABA regimen (HR = 0.52, P = 0.002) but had no difference when compared with ICS regimen (HR = 1.30, P = 0.286). The corticosteroid exposure in the daily ICS regimen was 2- to 5-fold compared with as-needed use of ICS/FABA regimen. CONCLUSIONS: Our analysis shows that the ICS/FABA as a symptom-driven therapy may be a promising alternative regimen for the patients with intermittent or mild asthma, but it needs further real-world RCTs to confirm these findings.

[Fast-onset antidepressant potentials of essential oil of herbs].

The existing antidepressants demonstrated delayed onset of clinical effects, so fast-onset antidepressants are required. Essential oil of herbs showed potentials fast-onset antidepressant potential. First, its aromatic odor can directly activate olfactory nerves; its high lipophilicity causes a high blood-brain barrier penetration rate; and its high volatility is suitable for nasal-brain targeting and inhalation delivery. Therefore, essential oils can rapidly regulate brain functions by multiple ways, suggesting a fast-onset antidepressant potential. Second, the advance of studies on chemistry and pharmacology of antidepressant essential oils demonstrated chemical substances, antidepressant effects and possible action mechanisms of antidepressant essential oils. Third, the effect of essential oils' antidepressant components on fast-onset antidepressant targets was investigated. It was found that chemical constituents of essential oils antagonized NMDA receptor activities, suggesting that essential oils have fast-onset antidepressant effect. Finally, characteristics of essential oils, fast-onset antidepressant targets and drug delivery methods are integrated to give full play to essential oils' fast-onset antidepressant advantage and provide a new direction for new drug discovery.

Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.

We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.

Fast onset of action of glycopyrronium compared with tiotropium in patients with moderate to severe COPD - A randomised, multicentre, crossover trial.

BACKGROUND: Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single-blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium. METHODS: In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 µg and tiotropium 18 µg via the Breezhaler® and Handihaler® devices, respectively. Primary objective was to demonstrate superiority of glycopyrronium over tiotropium in terms of improvement in forced expiratory volume in 1 s as assessed by the area under the curve from 0 to 2 h (FEV1 AUC 0-2h). Secondary endpoints were functional residual capacity (FRC), residual volume (RV), inspiratory capacity (IC), and specific airway resistance (sRaw), all measured by body plethysmography. RESULTS: Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV1 AUC0-2h (least squares mean treatment difference = 37 mL; 95% CI: 16, 59 mL; p < 0.01) and FEV1 at 15 min post-dose (least square mean treatment difference = 36 mL; 95% CI: 14, 58 mL; p < 0.01). Both treatments showed similar improvements in FRCpleth, RV, and IC. Glycopyrronium showed statistically significant improvement in sRaw compared with tiotropium over the first 90 min after dosing, with the difference of 0.184 kPa × s at 90 min post-dose (95% CI: 0.315,0.054 kPa × s; p < 0.01). CONCLUSIONS: Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV1 response seen with glycopyrronium. TRIAL REGISTRATION: ClinicalTrials.govNCT01922271.

Progress in potential targets for fast-onset antidepressants / 中国药理学与毒理学杂志

Depression has become a serious global public health concern and a prominent social problem.Moreover,the majority of first-line antidepressants that target monoamine neurotransmitter function have significant limitations (ie,low response rates,a time-lag of weeks for a response,cognitive impairment and sexual dysfunction),particularly with the delayed onset of clinical effects which will reduce the patients' clinical compliance and increase the patients' risk of suicide and self-harm.All this highlights a major unmet need for a new generation of antidepressants with fast onset action and low toxic side effects.There has been great progress in the study on pathogenesis of depression and drug targets so far.Recent research has shifted from increasing the level of monoamine neurotransmitter (NE/5-HT) to focusing on regulating the adaptive and plastic change of the nervous system,especially the discovery of new potential fast-onset non-monoaminergic targets including NMDA receptor,AMPA receptor and M choline receptor.This article reviews the investigation into generalized fast antidepressants and their potential targets,in the hope of providing critical information for the development of fastonset antidepressants.

Fast-onset antidepressant potentials of essential oil of herbs / 中国中药杂志

The existing antidepressants demonstrated delayed onset of clinical effects, so fast-onset antidepressants are required. Essential oil of herbs showed potentials fast-onset antidepressant potential. First, its aromatic odor can directly activate olfactory nerves; its high lipophilicity causes a high blood-brain barrier penetration rate; and its high volatility is suitable for nasal-brain targeting and inhalation delivery. Therefore, essential oils can rapidly regulate brain functions by multiple ways, suggesting a fast-onset antidepressant potential. Second, the advance of studies on chemistry and pharmacology of antidepressant essential oils demonstrated chemical substances, antidepressant effects and possible action mechanisms of antidepressant essential oils. Third, the effect of essential oils' antidepressant components on fast-onset antidepressant targets was investigated. It was found that chemical constituents of essential oils antagonized NMDA receptor activities, suggesting that essential oils have fast-onset antidepressant effect. Finally, characteristics of essential oils, fast-onset antidepressant targets and drug delivery methods are integrated to give full play to essential oils' fast-onset antidepressant advantage and provide a new direction for new drug discovery.

Early bronchodilator action of glycopyrronium versus tiotropium in moderate-to-severe COPD patients: a cross-over blinded randomized study (Symptoms and Pulmonary function in the moRnING).

BACKGROUND: Morning symptoms associated with COPD have a negative impact on patients' quality of life. Long-acting bronchodilators with rapid onset may relieve patients' symptoms. In the Symptoms and Pulmonary function in the moRnING study, we prospectively compared the rapid onset bronchodilator profile of glycopyrronium (GLY) and tiotropium (TIO) during the first few hours after dosing in patients with moderate-to-severe COPD. METHODS: Patients were randomized (1:1) to receive either once-daily GLY (50 µg) or TIO (18 µg) and corresponding placebos in a cross-over design for 28 days. The primary objective was to demonstrate the superiority of GLY versus TIO in area under the curve from 0 to 4 hours (AUC0-4h) forced expiratory volume in 1 second (FEV1) after the first dose. The secondary objective was to compare GLY versus TIO using the patient reported outcomes Morning COPD Symptoms Questionnaire 3 hours post-inhalation. RESULTS: One-hundred and twenty-six patients were randomized (male 70.2%; mean age 65.7 years) and 108 patients completed the study. On Day 1, GLY resulted in significantly higher FEV1 AUC0-4h after the first dose versus TIO (treatment difference [Δ], 0.030 L, 95% confidence interval 0.004-0.056, P=0.025). Improvements in morning COPD symptoms from baseline at Days 1 and 28 were similar between GLY and TIO. Post hoc analysis of the FEV1 AUC0-4h by time point on Day 1 showed significant improvements in patients receiving GLY versus TIO at 5 minutes (Δ=0.029 L, P=0.015), 15 minutes (Δ=0.033 L, P=0.026), and 1 hour (Δ=0.044 L, P=0.014). Safety results were comparable between both treatments. CONCLUSION: The SPRING study demonstrates the superiority of GLY versus TIO in terms of superior bronchodilation in the first 4 hours after administration, thus extending the clinical data that support a faster onset of action of GLY versus TIO.

Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.