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Advances in Therapy Apr 2024For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can... (Clinical Trial)
Clinical Trial
INTRODUCTION
For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety.
METHODS
The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases).
RESULTS
Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition.
CONCLUSIONS
Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment.
TRIAL REGISTRATION
ClinicalTrials.gov identifier, NCT04742699.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Japan; Prospective Studies; Triazoles; Azepines; Pyridines; Indenes; Pyrimidines
PubMed: 38460107
DOI: 10.1007/s12325-024-02811-2 -
Organic Letters Mar 2024In this report, we present a photopromoted, metal-free transannulation of phenyl azides for the synthesis of DNA-encoded seven-membered rings. The transformation is...
In this report, we present a photopromoted, metal-free transannulation of phenyl azides for the synthesis of DNA-encoded seven-membered rings. The transformation is efficiently achieved through a skeletal editing strategy targeting the benzene motif coupled with a Reversible Adsorption to Solid Support (RASS) strategy. A variety of valuable DNA-encoded seven-membered ring compounds, including DNA-encoded 3H-azepines, azepinones, and unnatural amino acids, are now accessible. Crucially, this DNA-compatible protocol can also be applied for the introduction of complex molecules, as exemplified by Lorcaserin and Betahistine. The selective conversion of readily available phenyl rings into high-value seven-membered rings offers a promising avenue for the construction of diversified and drug-like DNA-encoded library.
Topics: Benzene; Azides; Cyclization; Amines; DNA
PubMed: 38452132
DOI: 10.1021/acs.orglett.4c00377 -
Synapse (New York, N.Y.) Mar 2024Epileptic seizures are seen as a result of changing excitability balance depending on the deterioration in synaptic plasticity in the brain. Neuroplastin, and its...
Epileptic seizures are seen as a result of changing excitability balance depending on the deterioration in synaptic plasticity in the brain. Neuroplastin, and its related molecules which are known to play a role in synaptic plasticity, neurotransmitter activities that provide balance of excitability and, different neurological diseases, have not been studied before in epilepsy. In this study, a total of 34 Sprague-Dawley male and female rats, 2 months old, weighing 250-300 g were used. The epilepsy model in rats was made via pentylenetetrazole (PTZ). After the completion of the experimental procedure, the brain tissue of the rats were taken and the histopathological changes in the hippocampus and cortex parts and the brain stem were investigated, as well as the immunoreactivity of the proteins related to the immunohistochemical methods. As a result of the histopathological evaluation, it was determined that neuron degeneration and the number of dilated blood vessels in the hippocampus, frontal cortex, and brain stem were higher in the PTZ status epilepticus (SE) groups than in the control groups. It was observed that neuroplastin and related proteins TNF receptor-associated factor 6 (TRAF6), Gamma amino butyric acid type A receptors [(GABA(A)], and plasma membrane Ca2+ ATPase (PMCA) protein immunoreactivity levels increased especially in the male hippocampus, and only AMPA receptor subunit type 1 (GluA1) immunoreactivity decreased, unlike other proteins. We believe this may be caused by a problem in the mechanisms regulating the interaction of neuroplastin and GluA1 and may cause problems in synaptic plasticity in the experimental epilepsy model. It may be useful to elucidate this mechanism and target GluA1 when determining treatment strategies.
Topics: Animals; Female; Male; Rats; Brain Stem; Epilepsy; Hippocampus; Pentylenetetrazole; Rats, Sprague-Dawley; Receptors, GABA-A; TNF Receptor-Associated Factor 6; Plasma Membrane Calcium-Transporting ATPases; Receptors, AMPA; Cerebral Cortex
PubMed: 38436644
DOI: 10.1002/syn.22289 -
Journal of Ethnopharmacology Jun 2024Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in...
ETHNOPHARMACOLOGICAL RELEVANCE
Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated.
AIM OF THE STUDY
The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets.
MATERIALS AND METHODS
To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0-10 μM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CBR), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CBR antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CBR for M1 efficacy.
RESULTS
At a concentration of 400 μM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 μM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CBR activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist.
CONCLUSIONS
These results demonstrated that M1 as a potential CBR activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CBR chemical antagonism.
Topics: Humans; Rats; Animals; Proto-Oncogene Proteins c-akt; Glycosides; Zebrafish; Anticonvulsants; Phosphatidylinositol 3-Kinases; bcl-2-Associated X Protein; Brain-Derived Neurotrophic Factor; Molecular Docking Simulation; China; Seizures; Apoptosis Regulatory Proteins; Apoptosis; Proto-Oncogene Proteins c-bcl-2; Pentylenetetrazole; Neuroprotective Agents
PubMed: 38423411
DOI: 10.1016/j.jep.2024.117982 -
Biomedicine & Pharmacotherapy =... Apr 2024Salvia amarissima Ortega is a plant used in traditional medicine to treat CNS's affections. Despite its depressant properties in anxiety and fibromyalgia, there is no...
Salvia amarissima Ortega is a plant used in traditional medicine to treat CNS's affections. Despite its depressant properties in anxiety and fibromyalgia, there is no scientific evidence about its capability to control seizure activity. This study aimed to investigate the effects of the S. amarissima aqueous extract (SAAE) and its metabolite amarisolide A (AMA) on the electrocorticographic (ECoG) activity. The ECoG profiles were previously and concurrently analyzed to the pentylenetetrazole (85 mg/kg, i.p.)-induced seizure behavior after thirty min of the administration of several doses of the SAAE (1, 10, 30, and 100 mg/kg, i.p.) and two doses of AMA (0.5 and 1 mg/kg, i.p.). A dosage of AMA (1 mg/kg,i.p.) was selected to explore a possible mechanism of action by using antagonists of inhibitory receptors such as GABA (picrotoxin, 1 mg/kg, i.p.) or 5-HT of serotonin (WAY100635, 1 mg/kg, i.p.). Significant changes in the frequency bands and the spectral power were observed after the treatment alone. Additionally, SAAE and AMA produced significant and dose-dependent anticonvulsant effects by reducing the incidence and severity of seizures and increasing latency or survival. Both antagonists prevented the effects of AMA in the severity score of seizures and survival during the tonic-clonic seizures. In conclusion, our preclinical data support that S. amarissima possesses anticonvulsant properties, in part due to the presence of amarisolide A, mediated by different inhibitory mechanisms of action. Our scientific evidence suggests that this Salvia species and amarisolide A are potential neuroprotective alternatives to control seizures in epilepsy therapy.
Topics: Mice; Animals; Anticonvulsants; Salvia; Seizures; Pentylenetetrazole; Picrotoxin; Water; Dose-Response Relationship, Drug; Plant Extracts
PubMed: 38417289
DOI: 10.1016/j.biopha.2024.116352 -
Advanced Science (Weinheim,... Apr 2024One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated...
One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a-PSCs). These a-PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)-seq, Assays for Transposase-Accessible Chromatin (ATAC)-seq, and RNA-seq techniques, this work reveals that super-enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE-associated transcription with JQ1 reverses the activated phenotype of a-PSCs and decreases stromal fibrosis in both orthotopic and patient-derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL-12). In summary, this study not only elucidates the contribution of SEs of a-PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a-PSCs may become a gate-opening strategy that benefits PDAC drug therapy by removing stromal barriers.
Topics: Pancreatic Stellate Cells; Pancreatic Neoplasms; Humans; Animals; Mice; Immunotherapy; Tumor Microenvironment; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Gemcitabine; Deoxycytidine; Azepines; Cell Line, Tumor; Triazoles
PubMed: 38417121
DOI: 10.1002/advs.202308637 -
Molecular Diversity Feb 2024The synthesis of novel, high-yield derivatives of chromenoazepine was investigated in this work. CuO/TiO@MWCNTs was used as a nanocatalyst in a multicomponent reaction...
The synthesis of novel, high-yield derivatives of chromenoazepine was investigated in this work. CuO/TiO@MWCNTs was used as a nanocatalyst in a multicomponent reaction involving 4-aminocumarine, activated acetylenic chemicals, and alkyl bromide in room temperature water to create these novel compounds. Using MCRs of 4-aminocumarine, isothiocyanate, and alkyl bromide in the presence of CuO/TiO@MWCNTs as nanocatalysts in room-temperature water, chromenothiazepines were synthesized under comparable conditions. The freshly synthesized azepine exhibits antioxidant activity since its NH group has undergone two evaluation processes. Additionally, using two types of Gram-negative bacteria in a disk distribution procedure, the antibacterial activity of recently developed azepines was evaluated, and these compounds also inhibited the growth of Gram-positive bacteria. This method's benefits include quick reaction times, large product yields, and straightforward catalyst and product separation through easy steps.
PubMed: 38403738
DOI: 10.1007/s11030-023-10803-7 -
Behavioural Brain Research Apr 2024Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic...
Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration. Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment.
Topics: Animals; Anticonvulsants; Zebrafish; Pentylenetetrazole; Glutamic Acid; Serotonin; Seizures; Epilepsy; Carbamazepine; Levetiracetam; gamma-Aminobutyric Acid; Neurotransmitter Agents
PubMed: 38403178
DOI: 10.1016/j.bbr.2024.114920 -
Neuroscience Apr 2024The aim was to investigate the long-term effects of a single episode of immature Status Epilepticus (SE) on the excitability of the septal and temporal hippocampus in...
The aim was to investigate the long-term effects of a single episode of immature Status Epilepticus (SE) on the excitability of the septal and temporal hippocampus in vitro, by studying the relationship between interictal-like epileptiform discharges (IEDs) and high-frequency oscillations (HFOs; Ripples, Rs and Fast Ripples, FRs). A pentylenetetrazol-induced Status Epilepticus-(SE)-like generalized seizure was induced at postnatal day 20 in 22 male and female juvenile rats, sacrificed >40 days later to prepare hippocampal slices. Spontaneous IEDs induced by Mg-free ACSF were recorded from the CA3 area of temporal (T) or septal (S) slices. Recordings were band-pass filtered off-line revealing Rs and FRs and a series of measurements were conducted, with mean values compared with those obtained from age-matched controls (CTRs). In CTR S (vs T) slices, we recorded longer R & FR durations, a longer HFO-IED temporal overlap, higher FR peak power and more frequent FR initiation preceding IEDs (% events). Post-SE, in T slices all types of events duration (IED, R, FR) and the time lag between their onsets (R-IED, FR-IED, R-FR) increased, while FR/R peak power decreased; in S slices, the IED 1st population spike and the FR amplitudes, the R and FR peak power and the (percent) events where Rs or FRs preceded IEDs all decreased. The CA3 IED-HFO relationship offers insights to the septal-to-temporal synchronization patterns; its post-juvenile-SE changes indicate permanent modifications in the septotemporal excitability gradient. Moreover, these findings are in line to region-specific regulation of various currents post-SE, as reported in literature.
Topics: Male; Female; Rats; Animals; Status Epilepticus; Hippocampus; Seizures; Pentylenetetrazole; Electroencephalography
PubMed: 38401712
DOI: 10.1016/j.neuroscience.2024.02.019 -
Epilepsy Research Mar 2024Epilepsy represents a prevalent neurological disorder in the population, and the existing antiepileptic drugs (AEDs) often fail to adequately control seizures....
Epilepsy represents a prevalent neurological disorder in the population, and the existing antiepileptic drugs (AEDs) often fail to adequately control seizures. Inflammation is recognized as a pivotal factor in the pathophysiology of epilepsy. Luteolin, a natural flavonoid extract, possesses anti-inflammatory properties and exhibits promising neuroprotective activity. Nevertheless, the precise molecular mechanisms underlying the antiepileptic effects of luteolin remain elusive. In this study, we established a rat model of epilepsy using pentylenetetrazole (PTZ) to induce seizures. A series of behavioral experiments were conducted to assess behavioral abilities and cognitive function. Histological techniques, including HE staining, Nissl staining, and TUNEL staining, were employed to assess hippocampal neuronal damage. Additionally, Western blotting, RT-qPCR, and ELISA were utilized to analyze the expression levels of proteins involved in the TLR4/IκBα/NF-κB signaling pathway, transcription levels of apoptotic factors, and levels of inflammatory cytokines, respectively. Luteolin exhibited a dose-dependent reduction in seizure severity, prolonged the latency period of seizures, and shortened seizure duration. Furthermore, luteolin prevented hippocampal neuronal damage in PTZ-induced epileptic rats and partially restored behavioral function and learning and memory abilities. Lastly, PTZ kindling activated the TLR4/IκBα/NF-κB pathway, leading to elevated levels of the cytokines TNF-α, IL-6 and IL-1β, which were attenuated by luteolin. Luteolin exerted anticonvulsant and neuroprotective activities in the PTZ-induced epileptic model. Its mechanism was associated with the inhibition of the TLR4/IκBα/NF-κB pathway, alleviating the immune-inflammatory response in the post-epileptic hippocampus.
Topics: Rats; Animals; Pentylenetetrazole; NF-kappa B; NF-KappaB Inhibitor alpha; Toll-Like Receptor 4; Luteolin; Seizures; Signal Transduction; Epilepsy; Anticonvulsants; Cytokines
PubMed: 38382229
DOI: 10.1016/j.eplepsyres.2024.107321