-
MMWR. Morbidity and Mortality Weekly... Feb 2024
Topics: Humans; Neptune; New Jersey; Thiazepines; Cannabinoids
PubMed: 38300852
DOI: 10.15585/mmwr.mm7304a5 -
Regulatory Toxicology and Pharmacology... Mar 2024The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an...
The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an appropriate reference drug of abuse. Suvorexant, a Schedule IV dual orexin receptor antagonist was investigated for its potential use as a reference drug in Drug Discrimination Learning (DDL) studies. Firstly, toxicokinetic properties of suvorexant were determined in male and female rats after single oral doses of 160 and 325 mg/kg in MC and PEG400. Thereafter the subjective effects of suvorexant at 325 mg/kg versus vehicle were evaluated in a DDL paradigm and plasma exposures were measured. Mean maximum plasma exposures in male rats after a single dose of 325 mg/kg suvorexant were 2.5- (MC) to 10.5-fold (PEG400) the human exposure at supratherapeutic doses of 40 mg q.d. (C:1.1 μM), and 4.9- (MC) to 20.8-fold (PEG400) the approved maximum human efficacious dose (20 mg q.d.; 0.557 μM). Training male rats at 325 mg/kg in the DDL study however did not result in discriminative stimulus generalisation versus respective vehicles. Suvorexant, a Schedule IV dual orexin receptor antagonist failed to serve as a robust reference drug of abuse in the DDL paradigm in rats despite appropriate exposures.
Topics: Humans; Rats; Male; Female; Animals; Orexin Receptor Antagonists; Azepines; Triazoles
PubMed: 38286304
DOI: 10.1016/j.yrtph.2024.105570 -
Chemical Science Jan 2024The development of non-alternant nanographenes has attracted considerable attention due to their unique photophysical properties. Herein, we reported a novel aza-doped,...
The development of non-alternant nanographenes has attracted considerable attention due to their unique photophysical properties. Herein, we reported a novel aza-doped, non-alternant nanographene (NG) 1 by embedding the cycl[2,2,4]azine unit into the benzenoid NG framework. Single-crystal X-ray diffractometry suggests saddle or twisted nonplanar geometry of the entire backbone of 1 and coplanar conformation of the cycl[2,2,4]azine unit. DFT calculation together with solid structure indicates that NG 1 possesses significant local antiaromaticity in the azepine ring. By oxidative process or trifluoroacetic acid treatment, this nanographene can transform into a mono-radical cation, which was confirmed by UV/Vis absorption, H NMR, and electron paramagnetic resonance (EPR) spectroscopy. The antiaromaticity/aromaticity switching of the azepine ring on 1˙ from 1 enables the high stability of this radical cation, which remained intact for over 1 day. Due to the electron-donating nature of the nitrogen and the unique electronic structure, NG 1 exhibits strong electron-donating properties, as proved by the intermolecular charge transfer towards C with a high association constant. Furthermore, selective modification of NG 1 was accomplished by Vilsmeier reaction, and the derivatives 7 and 8 with substituted benzophenone were obtained. The photophysical and electronic properties can be tuned by the introduction of different electronic groups in benzophenone.
PubMed: 38274082
DOI: 10.1039/d3sc05515a -
ACS Chemical Neuroscience Feb 2024Plants used in traditional medicine in the management of epilepsy could potentially yield novel drug compounds with antiepileptic properties. The medicinal plant is...
Plants used in traditional medicine in the management of epilepsy could potentially yield novel drug compounds with antiepileptic properties. The medicinal plant is widely used in traditional medicine in the African continent, and epilepsy is among several indications. Limited knowledge is available on its toxicity and medicinal effects, such as anticonvulsant activities. This study explores the potential in vivo inhibition of seizure-like paroxysms and toxicity effects of dichloromethane (DCM) and ethanol (EtOH) extracts, as well as isolated xanthones and benzoates of . Ten phenolic compounds were isolated from the DCM extract. All of the substances were identified by nuclear magnetic resonance spectroscopy. Assays for toxicity and inhibition of pentylenetetrazole (PTZ)-induced seizure-like paroxysms were performed in zebrafish larvae. Among the compounds assessed in the assay for maximum tolerated concentration (MTC), benzyl-2-hydroxy-6-methoxy-benzoate (MTC 12.5 μM), 4,8-dihydroxy-1,2,3,5,6-pentamethoxyxanthone (MTC 25 μM), and 1,7-dihydroxy-4-methoxyxanthone (MTC 6.25 μM) were the most toxic. The DCM extract, 1,7-dihydroxy-4-methoxyxanthone and 2-hydroxy-1,7-dimethoxyxanthone displayed the most significant inhibition of paroxysms by altering the locomotor behavior in GABA receptor antagonist, PTZ, which induced seizures in larval zebrafish. The EtOH extract, benzyl benzoate, and benzyl-2-hydroxy-6-methoxy-benzoate unexpectedly increased locomotor activity in treated larval zebrafish and decreased locomotor activity in nontreated larval zebrafish, seemingly due to paradoxical excitation. The results reveal promising medicinal activities of this plant, contributing to our understanding of its use as an antiepileptic drug. It also shows us the presence of potentially new lead compounds for future drug development.
Topics: Animals; Zebrafish; Securidaca; Seizures; Anticonvulsants; Epilepsy; Plant Extracts; Pentylenetetrazole; Benzoates
PubMed: 38270158
DOI: 10.1021/acschemneuro.3c00642 -
Movement Disorders Clinical Practice Apr 2024Chronic constipation is a common digestive complication of Parkinson's disease (PD). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic constipation is a common digestive complication of Parkinson's disease (PD).
OBJECTIVES
To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD.
METHODS
This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed.
RESULTS
The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported.
CONCLUSIONS
Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation.
TRIAL REGISTRATION INFORMATION
Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).
Topics: Humans; Chronic Disease; Constipation; Dipeptides; Gastrointestinal Diseases; Parkinson Disease; Quality of Life; Thiazepines; Double-Blind Method
PubMed: 38264844
DOI: 10.1002/mdc3.13972 -
Neurological Sciences : Official... May 2024
Topics: Humans; Orexin Receptor Antagonists; Parkinson Disease; Azepines; Triazoles; Sleep Initiation and Maintenance Disorders
PubMed: 38231375
DOI: 10.1007/s10072-023-07261-2 -
Archives of Razi Institute Aug 2023Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological...
Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological diseases. In this regard, this study aimed to determine the effects of on pentylenetetrazol-induced epilepsy during the estrus cycle. For this purpose, 30 rats were randomly divided into five groups, namely control (saline), valproic acid (VPA, 75 mg/kg), (50 mg/kg), (100 mg/kg), and (150 mg/kg) with four subgroups (proestrus, estrus, metestrus, and diestrus). Subsequently, the initiation time of myoclonic seizures (ITMS), initiation time of tonic-clonic seizures (ITTS), and seizure duration (SD) were determined. According to the results, ITMS and ITTS significantly increased in the VPA-treated group (<0.05). (100 and 150 mg/kg) administration significantly increased ITMS and ITTS (<0.05). Moreover, the ITMS and ITTS in -treated rats were significantly higher in luteal phases, compared to the follicular phase (<0.05). In addition, pretreatment with VPA significantly decreased SD, compared to the control group (<0.05). A significant decrease in SD was observed in the rats pretreated with (100 and 150 mg/kg) (<0.05). Seizure duration significantly decreased in animals that received in luteal phases, compared to the follicular phase (<0.05). These results suggested that have anticonvulsant effects that are more prominent during the luteal phase than the follicular phase.
Topics: Animals; Female; Rats; Anticonvulsants; Estrus; Ginsenosides; Pentylenetetrazole; Seizures; Valproic Acid
PubMed: 38226383
DOI: 10.32592/ARI.2023.78.4.1359 -
Beilstein Journal of Organic Chemistry 2023A straightforward synthetic protocol for the efficient construction of diazepine-containing spiroindolines has been developed and proceeds through a by base-promoted...
A straightforward synthetic protocol for the efficient construction of diazepine-containing spiroindolines has been developed and proceeds through a by base-promoted annulation reaction of α-halogenated -acylhydrazones and isatin-derived MBH carbonates. The reaction mechanism of this formal [4 + 3] annulation includes the in situ generated allylic ylide, nucleophilic substitution, Michael additon, and elimination processes. Additionally, the similar reaction with α-halogenated -tosylhydrazones also afforded -tosyl-substituted spiro[indoline-3,5'-[1,2]diazepine] in satisfactory yields. This protocol provides a convenient approach for the assembly of diverse highly functionalized spiro[indoline-3,5'-[1,2]diazepines] and also features a broad substrate scope, simple reaction conditions, and high molecular convergence.
PubMed: 38170011
DOI: 10.3762/bjoc.19.143 -
Bioorganic Chemistry Feb 2024Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short-chain hemorphin peptide analogs containing non-natural amino acids....
Synthesis, molecular docking, electrochemical and fluorimetric analysis of new caffeic and cinnamic acid-conjugated hemorphin derivatives designed as potential anticonvulsant and antinociceptive agents.
Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short-chain hemorphin peptide analogs containing non-natural amino acids. They demonstrated anticonvulsant and antinociceptive activity with low neurotoxicity. In the present study, a series of novel bioconjugates of N-modified hemorphin analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetric analysis, in vivo anticonvulsant and antinociceptive activity in mice were conducted on the compounds. The three CA acid- (H4-CA, H5-CA, and H7-CA) and three KA acid- (H4-KA, H5-KA, and H7-KA) conjugated hemorphin derivatives exhibited potency at the highest doses of 2 µg/5 µl, administered by intracerebroventricular (icv) mode, against seizure spread in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate, at the lowest dose, was the only compound that suppressed clonic seizures in the subcutaneous pentylenetetrazol (scPTZ) test. Except for the H5-CA, all tested CA acid- and KA acid-conjugated peptide derivates had the potency to increase the latency for clonic seizures in a dose-dependent mode. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. All investigated peptides showed a more pronounced antinociceptive effect in the "intraplantar formalin" test compared to the "hot plate" test. Shorter chain analogs showed a better antinociceptive profile against tonic pain. The data suggest a DOR and KOR-mediated mechanism of action. According to the docking analysis, H7-CA showed a different antinociceptive profile than other investigated peptides. The novel peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA morphine peptides can be used to develop novel morphine-related analogs with anticonvulsant and antinociceptive activity.
Topics: Mice; Animals; Anticonvulsants; Molecular Docking Simulation; Seizures; Pentylenetetrazole; Analgesics; Electroshock; Peptides; Morphine Derivatives; Cinnamates
PubMed: 38150935
DOI: 10.1016/j.bioorg.2023.107063 -
BMC Medicine Dec 2023Exposure to general anesthesia influences neuronal functions during brain development. Recently, interneurons were found to be involved in developmental neurotoxicity by...
BACKGROUND
Exposure to general anesthesia influences neuronal functions during brain development. Recently, interneurons were found to be involved in developmental neurotoxicity by anesthetic exposure. But the underlying mechanism and long-term consequences remain elusive.
METHODS
Pregnant mice received 2.5% sevoflurane for 6-h on gestational day 14.5. Pentylenetetrazole (PTZ)-induced seizure, anxiety- and depression-like behavior tests were performed in 30- and 60-day-old male offspring. Cortical interneurons were labeled using Rosa26-EYFP/-; Nkx2.1-Cre mice. Immunofluorescence and electrophysiology were performed to determine the cortical interneuron properties. Q-PCR and in situ hybridization (ISH) were performed for the potential mechanism, and the finding was further validated by in utero electroporation (IUE).
RESULTS
In this study, we found that maternal sevoflurane exposure increased epilepsy susceptibility by using pentylenetetrazole (PTZ) induced-kindling models and enhanced anxiety- and depression-like behaviors in adolescent offspring. After sevoflurane exposure, the highly ordered cortical interneuron migration was disrupted in the fetal cortex. In addition, the resting membrane potentials of fast-spiking interneurons in the sevoflurane-treated group were more hyperpolarized in adolescence accompanied by an increase in inhibitory synapses. Both q-PCR and ISH indicated that CXCL12/CXCR4 signaling pathway downregulation might be a potential mechanism under sevoflurane developmental neurotoxicity which was further confirmed by IUE and behavioral tests. Although the above effects were obvious in adolescence, they did not persist into adulthood.
CONCLUSIONS
Our findings demonstrate that maternal anesthesia impairs interneuron migration through the CXCL12/CXCR4 signaling pathway, and influences the interneuron properties, leading to the increased epilepsy susceptibility in adolescent offspring. Our study provides a novel perspective on the developmental neurotoxicity of the mechanistic link between maternal use of general anesthesia and increased susceptibility to epilepsy.
Topics: Humans; Pregnancy; Female; Mice; Animals; Male; Sevoflurane; Pentylenetetrazole; Maternal Exposure; Interneurons; Epilepsy
PubMed: 38129829
DOI: 10.1186/s12916-023-03210-0