RESUMO
Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure-activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.
Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Pirazóis , Relação Estrutura-Atividade , Humanos , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/química , Antagonistas dos Receptores de Orexina/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Animais , Estrutura Molecular , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacocinética , Receptores de Orexina/metabolismo , Ratos , Relação Dose-Resposta a Droga , MasculinoRESUMO
(1) Background: Insomnia is a neurological illness that poses a significant threat to both physical and mental health. It results in the activation of neuroglial cells, heightened neuroinflammation, oxidative stress, and disruptions in the Hypothalamic-Pituitary-Adrenal (HPA) axis. Ligusticum Chuanxiong (CX) and Finger citron (FC) are frequently utilized botanicals for addressing sleeplessness. Both herbs possess notable anti-inflammatory properties in their volatile oils. However, their effectiveness is hindered by the nasal mucosal irritation and instability they exhibit. (2) Methods: This study involved the preparation of a nanofiber composite system using carbon nanofiber (CNF) suspensions containing essential oils of Ligusticum chuanxiong-Finger citron (CXEO-FCEO-CNF). The effects and mechanisms of these essential oils in improving insomnia were investigated using an insomnia mouse model after encapsulation. (3) Results: The CXEO-FCEO-CNF had an average particle size of 103.19 ± 1.64 nm. The encapsulation rates of essential oils of Ligusticum chuanxiong (CXEO) and essential oils of Finger citron (FCEO) were 44.50% and 46.15%, respectively. This resulted in a considerable improvement in the stability of the essential oils over a period of 30 days. The essential oils effectively decreased the irritation of the nasal mucosa following encapsulation. Furthermore, CXEO-FCEO-CNF enhanced voluntary activity and sleep in mice with insomnia, notably boosted the activity of superoxide dismutase (SOD), reduced the concentration of lipoxidized malondialdehyde (MDA), decreased the levels of hormones associated with the HPA axis, and regulated the levels of neurotransmitters, resulting in a beneficial therapeutic outcome. CXEO-FCEO-CNF contains a total of 23 active ingredients, such as alpha-Asarone, (E)-methyl isoeugenol, and Senkyunolide. These ingredients primarily work by modulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling system to decrease oxidative stress and inflammatory reactions. (4) Conclusions: This study presented initial evidence that the combination of CXEO and FCEO in nanofiber formulations effectively reduces the nasal mucosal irritation and instability of essential oils. Furthermore, it demonstrated the potential anti-neuroinflammatory and therapeutic effects of these formulations in treating insomnia. Overall, this study provides a theoretical foundation for developing new essential oil formulations derived from herbs.
Assuntos
Citrus , Modelos Animais de Doenças , Hipnóticos e Sedativos , Ligusticum , Nanofibras , Óleos Voláteis , Distúrbios do Início e da Manutenção do Sono , Animais , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Camundongos , Ligusticum/química , Nanofibras/química , Citrus/química , Masculino , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/metabolismo , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/química , Carbono/química , Estresse Oxidativo/efeitos dos fármacosRESUMO
Effective sedative drugs are in great demand due to increasing incidence of nervous disorders. The present work was aimed to develop a novel sublingual sedative drug based on glycine and L-tryptophan amino acids. Carbopol and different hydroxypropyl methylcellulose species were alternatively tested as mucoadhesive agents intended to prolong tryptophan sublingual release time. A model lipid medium of fully hydrated L-α-dimyristoylphosphatidylcholine was used for optimal mucoadhesive agents selection. Simultaneous processes of drug release and diffusion in lipid medium were first investigated involving both experimental and theoretical approaches. Individual substances, their selected combinations as well as different drug formulations were consecutively examined. Application of kinetic differential scanning calorimetry method allowed us to reveal a number of specific drug-excipient effects. Lactose was found to essentially facilitate tryptophan release and provide its ability to get into the bloodstream simultaneously with glycine, which is necessary to achieve glycine-tryptophan synergism. Introduction of a mucoadhesive agent into the formulation was shown to change kinetics of drug-membrane interactions variously depending on viscosity grade. Among the mucoadhesive agents, hydroxypropyl methylcellulose species K4M and E4M were shown to further accelerate drug release, therefore they were selected as optimal. Thus, effectiveness of the novel sedative drug was provided by including some excipients, such as lactose and the selected mucoadhesive agent species. A dynamic mathematical model was developed properly describing release and diffusion in lipid medium of various drug substances. Our study clearly showed applicability of a lipid medium to meet challenges such as drug-excipient interactions and optimization of drug formulations.
Assuntos
Excipientes , Glicina , Hipnóticos e Sedativos , Triptofano , Triptofano/química , Triptofano/administração & dosagem , Glicina/química , Glicina/administração & dosagem , Administração Sublingual , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacocinética , Excipientes/química , Liberação Controlada de Fármacos , Química Farmacêutica/métodos , Varredura Diferencial de Calorimetria , Lactose/química , Derivados da Hipromelose/química , Biofarmácia/métodos , Adesividade , ViscosidadeRESUMO
Zolpidem, N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide, is a hypnotic agent widely used in clinical practice but is detected in many clinical cases of fatal intoxication and suicide. In forensic toxicology, the precise determination of zolpidem concentration in blood is a must to provide concrete evidence of death by zolpidem poisoning. However, the concentrations of zolpidem in blood at autopsy often differ from those at the estimated time of death. In the present study, we found that zolpidem was degraded by hemoglobin (Hb) via the Fenton reaction at various temperatures. The mechanism underlying zolpidem degradation involved the oxidation of its linker moiety. The MS and MS/MS spectra obtained by liquid chromatography quadrupole-Orbitrap mass spectrometry (LC-Q-Orbitrap-MS) showed the formation of 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide (2-OH ZOL) in Hb/H2O2 solution incubated with zolpidem and in the blood of several individuals who died from ingestion of zolpidem. These results suggest that 2-OH ZOL is the post-mortem product of zolpidem degradation by Hb via the Fenton reaction.
Assuntos
Hemoglobinas , Peróxido de Hidrogênio , Espectrometria de Massas em Tandem , Zolpidem , Zolpidem/metabolismo , Humanos , Hemoglobinas/metabolismo , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/química , Toxicologia Forense/métodos , Piridinas/sangue , Autopsia , Cromatografia Líquida , Oxirredução , Mudanças Depois da Morte , Ferro/metabolismoRESUMO
BACKGROUND: Pyridine and its derivatives play a vital role in medicinal chemistry, serving as key scaffolds for drugs. The ability to bind to biological targets makes pyridine compounds significant, sparking interest in creating new pyridine-based drugs. Thus, the purpose of the research is to synthesize new thioalkyl derivatives of pyridine, predict their biological spectrum, study their psychotropic properties, and based on these findings, perform structure-activity relationships to assess pharmacophore functional groups. METHODS: Classical organic methods were employed for synthesizing new thioalkyl derivatives of pyridine, with a multifaceted pharmacological profiles. Various software packages and methods were employed to evaluate the biological spectrum of the newly synthesized compounds. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. RESULTS: Effective synthetic methods for 6-amino-4-phenyl-2-thio-2H-thiopyran-5-carboxylic acid ethyl ester, 2-amino substituted thiopyridine derivatives and 6-cycloamino-2-thioalkyl-4-phenylnicotinate derivatives were obtained in high yield. Predicted biological spectra and pharmacokinetic data indicated high gastrointestinal absorption and low blood-brain barrier passage for most compounds and demonstrated potential various biological effects, particularly psychotropic properties. Studied compounds demonstrated high anticonvulsant activity through antagonism with pentylenetetrazole. They exhibited low toxicity without inducing muscle relaxation in the studied doses. In psychotropic studies, the compounds displayed activating, sedative, and anxiolytic effects. Notably, the 6-amino-2-thioalkyl-4-phenylnicotinate derivatives demonstrated significant anxiolytic activity (about four times more compared to diazepam). They also exhibited pronounced sedative effects. Ethyl 2-({2-[(diphenylmethyl)amino]-2-oxoethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate exhibited anxiolytic activity even two times greater than diazepam. Moreover, all studied compounds showed statistically significant antidepressant effects. Noteworthy ethyl 2-({2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate showcasing its unique psychotropic effect. CONCLUSIONS: The selected compounds demonstrate anticonvulsant properties, activating behavior, and anxiolytic effects, while simultaneously exhibiting antidepressant effects and these compounds as promising candidates for further exploration in the development of therapeutics with a broad spectrum of neuropsychiatric applications.
Assuntos
Ansiolíticos , Anticonvulsivantes , Piridinas , Relação Estrutura-Atividade , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Camundongos , Ansiolíticos/farmacologia , Ansiolíticos/síntese química , Ansiolíticos/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Masculino , Convulsões/tratamento farmacológico , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , PentilenotetrazolRESUMO
Xylazine (also known as "tranq") is a potent nonopioid veterinary sedative that has recently experienced a surge in use as a drug adulterant, most often combined with illicitly manufactured fentanyl. This combination may heighten the risk of fatal overdose. Xylazine has no known antidote approved for use in humans, and age-adjusted overdose deaths involving xylazine were 35 times higher in 2021 than 2018. In April 2023, the Biden Administration declared xylazine-laced fentanyl an emerging drug threat in the United States. In 2022, the Drug Enforcement Agency (DEA) reported nearly a quarter of seized fentanyl powder contained xylazine. This dramatic increase in prevalence has solidified the status of xylazine as an emerging drug of abuse and an evolving threat to public health. The following narrative review outlines the synthesis, pharmacokinetics, pharmacodynamics, and adverse effects of xylazine, as well as the role it may play in the ongoing opioid epidemic.
Assuntos
Xilazina , Xilazina/farmacologia , Humanos , Animais , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/química , Fentanila/farmacologia , Fentanila/química , Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Overdose de Drogas/epidemiologiaRESUMO
Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.
Assuntos
Receptores Opioides kappa , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Animais , Camundongos , Relação Estrutura-Atividade , Masculino , Humanos , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , Ratos , Analgésicos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Descoberta de Drogas , Ratos Sprague-Dawley , CricetulusRESUMO
BACKGROUND: Five Polyporales mushrooms, namely Amauroderma rugosum, Ganoderma lucidum, G. resinaceum, G. sinense and Trametes versicolor, are commonly used in China for managing insomnia. However, their active components for this application are not fully understood, restricting their universal recognition. PURPOSE: In this study, we aimed to identify sedative-hypnotic compounds shared by these five Polyporales mushrooms. STUDY DESIGN AND METHODS: A UPLC-Q-TOF-MS/MS-based untargeted metabolomics, including OPLS-DA (orthogonal projection of potential structure discriminant analysis) and OPLS (orthogonal projections to latent structures) analysis together with mouse assays, were used to identify the main sedative-hypnotic compounds shared by the five Polyporales mushrooms. A pentobarbital sodium-induced sleeping model was used to investigate the sedative-hypnotic effects of the five mushrooms and their sedative-hypnotic compounds. RESULTS: Ninety-two shared compounds in the five mushrooms were identified. Mouse assays showed that these mushrooms exerted sedative-hypnotic effects, with different potencies. Six triterpenes [four ganoderic acids (B, C1, F and H) and two ganoderenic acids (A and D)] were found to be the main sedative-hypnotic compounds shared by the five mushrooms. CONCLUSION: We for the first time found that these six triterpenes contribute to the sedative-hypnotic ability of the five mushrooms. Our novel findings provide pharmacological and chemical justifications for the use of the five medicinal mushrooms in managing insomnia.
Assuntos
Hipnóticos e Sedativos , Metabolômica , Polyporales , Espectrometria de Massas em Tandem , Animais , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/química , Camundongos , Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Polyporales/química , Masculino , Agaricales/química , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Reishi/químicaRESUMO
Photoaffinity ligands are best known as tools used to identify the specific binding sites of drugs to their molecular targets. However, photoaffinity ligands have the potential to further define critical neuroanatomic targets of drug action. In the brains of WT male mice, we demonstrate the feasibility of using photoaffinity ligands in vivo to prolong anesthesia via targeted yet spatially restricted photoadduction of azi-m-propofol (aziPm), a photoreactive analog of the general anesthetic propofol. Systemic administration of aziPm with bilateral near-ultraviolet photoadduction in the rostral pons, at the border of the parabrachial nucleus and locus coeruleus, produced a 20-fold increase in the duration of sedative and hypnotic effects compared with control mice without UV illumination. Photoadduction that missed the parabrachial-coerulean complex also failed to extend the sedative or hypnotic actions of aziPm and was indistinguishable from nonadducted controls. Paralleling the prolonged behavioral and EEG consequences of on target in vivo photoadduction, we conducted electrophysiologic recordings in rostral pontine brain slices. Using neurons within the locus coeruleus to further highlight the cellular consequences of irreversible aziPm binding, we demonstrate transient slowing of spontaneous action potentials with a brief bath application of aziPm that becomes irreversible on photoadduction. Together, these findings suggest that photochemistry-based strategies are a viable new approach for probing CNS physiology and pathophysiology.SIGNIFICANCE STATEMENT Photoaffinity ligands are drugs capable of light-induced irreversible binding, which have unexploited potential to identify the neuroanatomic sites of drug action. We systemically administer a centrally acting anesthetic photoaffinity ligand in mice, conduct localized photoillumination within the brain to covalently adduct the drug at its in vivo sites of action, and successfully enrich irreversible drug binding within a restricted 250 µm radius. When photoadduction encompassed the pontine parabrachial-coerulean complex, anesthetic sedation and hypnosis was prolonged 20-fold, thus illustrating the power of in vivo photochemistry to help unravel neuronal mechanisms of drug action.
Assuntos
Anestésicos Intravenosos , Encéfalo , Hipnose , Hipnóticos e Sedativos , Ligantes , Marcadores de Fotoafinidade , Propofol , Animais , Masculino , Camundongos , Neurônios Adrenérgicos/efeitos dos fármacos , Anestesia Intravenosa , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Eletrocorticografia , Eletroencefalografia , Hipnose/métodos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/efeitos da radiação , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Locus Cerúleo/efeitos da radiação , Camundongos Endogâmicos C57BL , Núcleos Parabraquiais/efeitos dos fármacos , Núcleos Parabraquiais/metabolismo , Núcleos Parabraquiais/efeitos da radiação , Marcadores de Fotoafinidade/química , Marcadores de Fotoafinidade/efeitos da radiação , Propofol/administração & dosagem , Propofol/análogos & derivados , Propofol/farmacologia , Propofol/efeitos da radiação , Fatores de Tempo , Raios Ultravioleta , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/química , Anestésicos Intravenosos/farmacologia , Anestésicos Intravenosos/efeitos da radiaçãoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia limbata C. A. Mey. (Persian name: Maryam Goli-e-labeh dar) has been used for treating central nervous disorders such as insomnia, anxiety and depression in Persian traditional medicine. S. limbata is known for its pharmacological activities which could be at least in a part, upon the presence of rosmarinic acid (RA). However, the sedative-hypnotic effect, anxiolytic activity, possible side effects, and the mechanism of action of S. limbata extract has not yet been examined. AIM OF THE STUDY: In the current study the sedative-hypnotic effect, anxiolytic activity, possible side effects, and the mechanism of action of S. limbata extracts were evaluated. Besides, the effects of altitude and phenological stage on the RA content of S. limbata were investigated. MATERIALS AND METHODS: Sedative-hypnotic and anxiolytic effects were evaluated through the pentobarbital induced loss of righting reflex test and open field test, respectively. Flumazenil was used to reveal the mechanism of action. Possible side effects were investigated in the passive avoidance and grip strength tests. Besides, the effects of altitude and phenological stage (vegetative, flowering, and seed setting) on the RA content of S. limbata were evaluated using reversed-phase high-performance liquid chromatography (RP-HPLC). RESULTS: Following behavioral tests, sedative-hypnotic and anxiolytic effects were observed. Since the observed effects were reversed by flumazenil and no side effect on the memory and muscle strength was reported, modulation of the α1-containing GABA-A receptors could be proposed as one of the involved mechanisms. According to the RP-HPLC analysis, harvesting S. limbata in the vegetative stage at the altitude of 2500 m led to the highest content of RA (8.67 ± 0.13 mg/g dry matter). Among different extract of the plant samples collected in the vegetative stage at the altitude of 2500 m, the hydroalcoholic extract showed the highest rosmarinic acid content. CONCLUSION: The obtained results help to find the optimum situation to gain the highest content of RA as well as the pharmacological activity that could be economically important for the pharmaceutical industries.
Assuntos
Cinamatos/química , Depsídeos/química , Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Salvia/química , Altitude , Animais , Antídotos/farmacologia , Diazepam/química , Diazepam/farmacologia , Flumazenil/farmacologia , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/química , Masculino , Memória/efeitos dos fármacos , Camundongos , Componentes Aéreos da Planta , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Testes de Toxicidade , Ácido RosmarínicoRESUMO
Hops contain flavonoids that have sedative and sleep-promoting activities such as α-acid, ß-acid, and xanthohumol. In this study, the sleep-enhancing activity of a Saaz-Saphir hops mixture was measured. In the caffeine-induced insomnia model, the administration of a Saaz-Saphir mixture increased the sleep time compared to Saaz or Saphir administration alone, which was attributed to the increase in NREM sleep time by the δ-wave increase. Oral administration of the Saaz-Saphir mixture for 3 weeks increased the γ-amino butyric acid (GABA) content in the brain and increased the expression of the GABAA receptor. As the GABA antagonists picrotoxin and bicuculline showed a decrease in sleep activity, it was confirmed that the GABAA receptor was involved in the Saaz-Saphir mixture activity. In addition, the GABAA receptor antagonist also reduced the sleep activity induced by xanthohumol and humulone contained in the Saaz-Saphir mixture. Therefore, xanthohumol and humulone contained in the Saaz-Saphir mixture showed sleep-promoting activity mediated by the GABAA receptors. The mixture of the Saaz and Saphir hop varieties may thus help mitigate sleep disturbances compared to other hop varieties.
Assuntos
Cicloexenos/farmacologia , Flavonoides/farmacologia , Humulus/química , Propiofenonas/farmacologia , Receptores de GABA-A/genética , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Terpenos/farmacologia , Ácidos/química , Animais , Bicuculina/farmacologia , Cafeína/efeitos adversos , Cicloexenos/química , Modelos Animais de Doenças , Eletroencefalografia , Flavonoides/química , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/farmacologia , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Camundongos , Picrotoxina/farmacologia , Propiofenonas/química , Sono/efeitos dos fármacos , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/patologia , Terpenos/química , Ácido gama-Aminobutírico/genéticaRESUMO
BACKGROUND: Ganoderma (Lingzhi in Chinese) has shown good clinical outcomes in the treatment of insomnia, restlessness, and palpitation. However, the mechanism by which Ganoderma ameliorates insomnia is unclear. We explored the mechanism of the anti-insomnia effect of Ganoderma using systems pharmacology from the perspective of central-peripheral multi-level interaction network analysis. METHODS: The active components and central active components of Ganoderma were obtained from the TCMIP and TCMSP databases, then screened to determine their pharmacokinetic properties. The potential target genes of these components were identified using the Swiss Target Prediction and TCMSP databases. The results were matched with the insomnia target genes obtained from the GeneCards, OMIM, DisGeNET, and TCMIP databases. Overlapping targets were subjected to multi-level interaction network analysis and enrichment analysis using the STRING, Metascape, and BioGPS databases. The networks analysed were protein-protein interaction (PPI), drug-component-target gene, component-target gene-organ, and target gene-extended disease; we also performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. RESULTS: In total, 34 sedative-hypnotic components (including 5 central active components) were identified, corresponding to 51 target genes. Multi-level interaction network analysis and enrichment analysis demonstrated that Ganoderma exerted an anti-insomnia effect via multiple central-peripheral mechanisms simultaneously, mainly by regulating cell apoptosis/survival and cytokine expression through core target genes such as TNF, CASP3, JUN, and HSP90αA1; it also affected immune regulation and apoptosis. Therefore, Ganoderma has potential as an adjuvant therapy for insomnia-related complications. CONCLUSION: Ganoderma exerts an anti-insomnia effect via complex central-peripheral multi-level interaction networks.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Ganoderma/química , Distúrbios do Início e da Manutenção do Sono , Bases de Dados Genéticas , Bases de Dados de Produtos Farmacêuticos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Redes Reguladoras de Genes/efeitos dos fármacos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Farmacologia em Rede , Mapas de Interação de Proteínas/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/genética , Distúrbios do Início e da Manutenção do Sono/metabolismoRESUMO
Rhodiola rosea L. (Crassulaceae) are popularly used as a natural supplement for the treatment of insomnia and anxiety. Here, saponin extracts from R. rosea were investigated for their roles on relieving sleeplessness. The levels of neurotransmitters, hormones, and inflammation cytokines in plasma, and the expression of 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), prostaglandin D2 (PGD2), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in the hypothalamus and hippocampus were detected using ELISA, RT-PCR, and western blotting. First, the butanol fraction extracted from R. rosea was collected as the total saponins (HJT-I), then a saponin-rich fraction (HJT-II) was obtained after the further purification of HJT-I. The saponin contents of HJT-I and HJT-II were 28.92% and 65.69%, respectively. Second, behavioral tests were performed and showed that both HJT-I and HJT-II could effectively reduce the duration of immobility in the tail suspension test, and shorten sleep latency and prolong the sleep duration time in the sodium barbital-induced sleeping test, with HJT-II better than HJT-I. Third, ELLISA results showed that the concentrations of GABA, 5-HT, norepinephrine (NA), PGD2, and IL-1ß in plasma were significantly increased after HJT-I and HJT-II administration, while IL-6 was decreased. HJT-I and HJT-II also exhibited differential modulation of the receptors of 5-HT, GABA, PGD2, and IL-1ß expression. In hypothalamus, HJT-II was more powerful than HJT-I in regulation of the GABAARα2, GABAARα3, and glutamic acid decarboxylase (GAD) 65/67 expression, as well as 5-HT2A and IL-1ß. As for DPR and PGD2, HJT-II was more effective in the hippocampus. The efficacy of HJT-I was better than HJT-II at stimulating GABAARα2, GAD 65/67, 5-HT1A, and IL-1ß expression in the hippocampus. In conclusion, the potential sedative and hypnotic effects of HJT-I and HJT-II may possibly be related to the serotonergic, GABAAergic, and immune systems, while the underlying mechanism of HJT-I and HJT-II differed from each other.
Assuntos
Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Rhodiola/química , Saponinas/farmacologia , Sono/efeitos dos fármacos , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hipnóticos e Sedativos/química , Masculino , Fitoterapia , Extratos Vegetais/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Saponinas/química , Ácido gama-Aminobutírico/metabolismoRESUMO
Lipoic acid (LA) is globally known and its supplements are widely used. Despite its importance for the organism it is not considered a vitamin any more. The multiple metabolic forms and the differences in kinetics (absorption, distribution and excretion), as well as the actions of its enantiomers are analysed in the present article together with its biosynthetic path. The proteins involved in the transfer, biotransformation and activity of LA are mentioned. Furthermore, the safety and the toxicological profile of the compound are commented, together with its stability issues. Mechanisms of lipoic acid intervention in the human body are analysed considering the antioxidant and non-antioxidant characteristics of the compound. The chelating properties, the regenerative ability of other antioxidants, the co-enzyme activity and the signal transduction by the implication in various pathways will be discussed in order to be elucidated the pleiotropic effects of LA. Finally, lipoic acid integrating analogues are mentioned under the scope of the multiple pharmacological actions they acquire towards degenerative conditions.
Assuntos
Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Antipsicóticos/metabolismo , Quelantes/metabolismo , Hipnóticos e Sedativos/metabolismo , Hipoglicemiantes/metabolismo , Agentes de Imunomodulação/metabolismo , Ácido Tióctico/análogos & derivados , Ácido Tióctico/metabolismo , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/química , Antioxidantes/efeitos adversos , Antioxidantes/química , Antipsicóticos/efeitos adversos , Antipsicóticos/química , Quelantes/efeitos adversos , Quelantes/química , Suplementos Nutricionais , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/química , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/química , Agentes de Imunomodulação/efeitos adversos , Agentes de Imunomodulação/química , Cinética , Oxirredução , Transdução de Sinais , Ácido Tióctico/efeitos adversos , Ácido Tióctico/químicaRESUMO
Although Zhusha Anshen Pill (ZSASP) is a commonly used traditional prescription for insomnia, the safety of cinnabar in the formula has always been controversial since its initial application in medical fields. Here, we developed a new prescription, Tieshuang Anshen Prescription (TSASP), by improving ZSASP with Fe2+ instead of Hg2+. Besides, TSASP was further optimized by establishing and testing the HPLC fingerprint and its sedative-hypnotic effect of formulas with different compatibility ratios and performing correlation spectrum analysis. The safety of TSASP was also evaluated by HE staining of liver and kidney. In addition, a validated and robust UHPLC-MS/MS method was established to demonstrate the pharmacokinetic characteristics of berberine, palmatine, jatrorrhizine, ligustilide, catalpol, loganin, liquiritin and liquiritigenin after oral administration of TSASP. Our study originally provides a new non-toxic prescription, TSASP, with better sedative-hypnotic effect in comparison with ZSASP, revealing that Fe2+ could replace Hg2+ to eliminate its toxicity and play a sedative role. Meanwhile, we believe that our pharmacokinetics results may contribute valuable reference to both TSASP's specific mechanism of action and its further clinical efficacy and effectiveness research.
Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Hipnóticos e Sedativos/farmacocinética , Ferro/farmacocinética , Locomoção/efeitos dos fármacos , Mercúrio/farmacocinética , Sono/efeitos dos fármacos , Animais , Animais não Endogâmicos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Feminino , Hipnóticos e Sedativos/análise , Hipnóticos e Sedativos/química , Ferro/análise , Ferro/química , Locomoção/fisiologia , Masculino , Mercúrio/análise , Mercúrio/química , Compostos de Mercúrio/análise , Compostos de Mercúrio/química , Compostos de Mercúrio/farmacocinética , Camundongos , Ratos , Ratos Wistar , Sono/fisiologiaRESUMO
The functional food market is growing with a compound annual growth rate of 7.9%. Thai food recipes use several kinds of herbs. Lemongrass, garlic, and turmeric are ingredients used in Thai curry paste. Essential oils released in the preparation step create the flavor and fragrance of the famous tom yum and massaman dishes. While the biological activities of these ingredients have been investigated, including the antioxidant, anti-inflammatory, and antimicrobial activities, there is still a lack of understanding regarding the responses to the essential oils of these plants. To investigate the effects of essential oil inhalation on the brain and mood responses, electroencephalography was carried out during the non-task resting state, and self-assessment of the mood state was performed. The essential oils were prepared in several dilutions in the range of the supra-threshold level. The results show that Litsea cubeba oil inhalation showed a sedative effect, observed from alpha and beta wave power reductions. The frontal and temporal regions of the brain were involved in the wave alterations. Garlic oil increased the alpha wave power at lower concentrations; however, a sedative effect was also observed at higher concentrations. Lower dilution oil induced changes in the fast alpha activity in the frontal region. The alpha and beta wave powers were decreased with higher dilution oils, particularly in the temporal, parietal, and occipital regions. Both Litsea cubeba and turmeric oils resulted in better positive moods than garlic oil. Garlic oil caused more negative moods than the others. The psychophysiological activities and the related brain functions require further investigation. The knowledge obtained from this study may be used to design functional food products.
Assuntos
Afeto/efeitos dos fármacos , Curcuma/química , Lobo Frontal/fisiologia , Alho/química , Litsea/química , Óleos Voláteis/administração & dosagem , Lobo Temporal/fisiologia , Administração por Inalação , Ondas Encefálicas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletroencefalografia , Feminino , Lobo Frontal/efeitos dos fármacos , Alimento Funcional/análise , Alimento Funcional/economia , Cromatografia Gasosa-Espectrometria de Massas , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Odorantes , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Óleos de Plantas/administração & dosagem , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Descanso/fisiologia , Lobo Temporal/efeitos dos fármacos , Tailândia , Adulto JovemRESUMO
The accidental ingestion of drugs is a common concern, especially in the case of young children. A physiologically based pharmacokinetic (PBPK) model that implements the age-dependent size growth and ontogeny of organ functions can be used to predict the concentration-time profiles of drugs in the pediatric population. In this study, the feasibility of using a PBPK model for predicting the amount of drug accidentally swallowed by a child was assessed based on a case study in an infant. Alprazolam was the drug involved in the current case. The developed PBPK model of alprazolam was first evaluated using pharmacokinetic data obtained in healthy adult male volunteers. Then, it was adapted for application to virtual Japanese pediatric subjects having the same demographic information as the infant of interest. The pharmacokinetic data observed in the infant fell within the range of the 5th and 95th percentiles of the pharmacokinetic simulations after administration of 0.4 mg alprazolam (equivalent to one tablet) in the panel of virtual infants. PBPK simulations could provide estimates of the amount accidentally ingested by a child and also give mechanistic insights into the observed drug concentrations. The current study demonstrates the potential clinical utility of PBPK modeling.
Assuntos
Alprazolam , Distúrbios Induzidos Quimicamente , Simulação por Computador , Inativação Metabólica/fisiologia , Taxa de Depuração Metabólica/fisiologia , Acidentes Domésticos , Alprazolam/química , Alprazolam/metabolismo , Alprazolam/farmacocinética , Biomarcadores Farmacológicos/sangue , Distúrbios Induzidos Quimicamente/diagnóstico , Distúrbios Induzidos Quimicamente/metabolismo , Citocromo P-450 CYP3A/genética , Ingestão de Alimentos , Feminino , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/metabolismo , Hipnóticos e Sedativos/farmacocinética , Lactente , Modelos Biológicos , Eliminação RenalRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Stress is a state of feeling that inhibits one from responding properly in the face of a threat. Agarwood smoke has been used in traditional medicine as a sedative anti-anxious, and anti-restless therapy. Its scent emitted from heat induces people to enter a stable state; however, the underlying molecular effect is still unclear. AIM OF THE STUDY: This study analyzed novel biological events and gene expression signatures induced by agarwood incense smoke in mice. MATERIALS AND METHODS: Incense smoke was produced by heating at 150 °C for 30 min in a headspace autosampler oven. We treated mice with exposure to incense smoke from Kynam agarwood for 45 min/day for 7 consecutive days. After a 7-day inhalation period, the potent agarwood smoke affected-indicators in serum were measured, and the RNA profiles of the mouse brains were analyzed by microarray to elucidate the biological events induced by agarwood incense smoke. RESULTS: Chemical profile analysis showed that the major component in the incense smoke of Kynam was 2-(2-phenylethyl) chromone (26.82%). Incense smoke from Kynam induced mice to enter a stable state and increased the levels of serotonin in sera. The emotion-related pathways, including dopaminergic synapse, serotonergic synapse, GABAergic synapse, long-term depression and neuroactive ligand-receptor interaction, were significantly affected by incense smoke. Moreover, the expression of Crhr2 and Chrnd genes, involved with neuroactive ligand-receptor interaction pathway, was upregulated by incense smoke. CONCLUSIONS: By a newly-established incense smoke exposure system, we first identified that anti-anxious and anti-depressant effects of agarwood incense smoke were likely associated with the increase of serotonin levels and multiple neuroactive pathways in mice.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Serotonina/metabolismo , Fumaça/análise , Madeira/química , Animais , Ansiolíticos/química , Ansiolíticos/uso terapêutico , Antidepressivos/química , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Emoções/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/uso terapêutico , Masculino , Medicina Tradicional , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
The methanol extract and its ethyl acetate fraction (EAF) of Actaea acuminata (Wall. ex. Royle) H. Hara roots were reported to exhibit significant antianxiety, anticonvulsant and antidepressant activities, and mild sedative activity. But the constituents responsible for these activities have not been isolated. The present study was undertaken to isolate neuroprotective compounds of A. acuminata following bioactivity-guided-fractionation. The column chromatography of EAF and its sub-fractions led to the isolation of four phenolic compounds (bergenin, gallic acid, acetyl bergenin and racemic mixture of diacetyl bergenin), which were characterized by IR and NMR spectral analysis. All the compounds exhibited significant antianxiety and antidepressant activities with respect to control. The gallic acid and bergenin did not show anticonvulsant activity, whereas acetyl bergenin and racemic mixture of diacetyl bergenin exhibited significant anticonvulsant activity. Neuropharmacological activities of A. acuminata are attributed due to polyphenolic compounds. Scientific validation of traditional claims of A. acuminata has opened up roadmap of research for the development of CNS affecting lead molecules.
Assuntos
Actaea/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Espectroscopia de Prótons por Ressonância Magnética/métodos , Espectrofotometria Infravermelho/métodosRESUMO
The slowness of dripping and the presence of alcohol have been offered/suggested as possible causes for the increased risk of developing dependence to the oral formulation of lormetazepam rather than to other anxiolytic and hypnotic drugs. We hence assessed the time of dripping of the most used benzodiazepines and z-drugs oral solution products under experimental conditions and the different employed excipients through a comparative analysis of the Summaries of Product Characteristics. A wide range of the median overall dispensing time was found across the eight products included in the analysis. Among the products containing LMZ, Minias® ranked in the fourth position, while LMZ Mylan Generics® and Noctamid® in the sixth and third, respectively. Our data suggest that the pace of dripping and the presence of alcohol cannot be considered themselves the cause that triggered the abuse of lormetazepam. More precisely, the quantity of alcohol per bottle has been found negligible at therapeutic doses; however, when these are exceeded, they may have clinical implications for patients. Further studies are needed to assess them. Meanwhile, the public-health problem remains and some improvements should be carried out at different levels, to guarantee the appropriate prescription and use of lormetazepam oral solution.