-
Scientific Reports Jun 2024Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of...
Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of these pathways. Trigonelline (TRG) has been shown to possess various pharmacological effects like neuroprotection. Therefore, this study was performed to determine TRG's anticonvulsant effects, focusing on its potential effects on N-methyl-D-aspartate (NMDA) receptors, a type of glutamate receptor, and oxidative stress state in the prefrontal cortex (PFC) in PTZ-induced seizure in mice. Seventy-two male mice were randomly divided into nine groups. The groups included mice that received normal saline, TRG at doses of 10, 50, and 100 mg/kg, diazepam, NMDA (an agonist), ketamine (an antagonist), the effective dose of TRG with NMDA, as well as sub-effective dose of TRG with ketamine, respectively. All agents were administrated intraperitoneally 60 min before induction of seizures by PTZ. Latency to seizure, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels in serum and PFC were measured. Furthermore, the gene expression of NR2A and NR2B, subunits of NMDA receptors, was measured in the PFC. TRG administration increased the latency to seizure onset and enhanced TAC while reducing MDA levels in both the PFC and serum. TRG also decreased the gene expression of NR2B in the PFC. Unexpectedly, the findings revealed that the concurrent administration of ketamine amplified, whereas NMDA mitigated, the impact of TRG on latency to seizure. Furthermore, NMDA diminished the positive effects of TRG on antioxidant capacity and oxidative stress, while ketamine amplified these beneficial effects, indicating a complex interaction between TRG and NMDA receptor modulation. In the gene expression of NMDA receptors, results showed that ketamine significantly decreased the gene expression of NR2B when co-administrated with a sub-effective dose of TRG. It was found that, at least partially, the anticonvulsant effect of TRG in PTZ-induced seizures in male mice was mediated by the attenuation of glutamatergic neurotransmission as well as the reduction of oxidative stress.
Topics: Animals; Receptors, N-Methyl-D-Aspartate; Oxidative Stress; Anticonvulsants; Mice; Male; Alkaloids; Seizures; Prefrontal Cortex; Malondialdehyde; Ketamine; Pentylenetetrazole; Antioxidants
PubMed: 38902338
DOI: 10.1038/s41598-024-65301-z -
Molecules (Basel, Switzerland) May 2024Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is...
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.
Topics: Animals; Zebrafish; Anticonvulsants; Disease Models, Animal; Pentylenetetrazole; Epilepsy; Seizures; Electroencephalography; Valproic Acid; Larva; Brain; Inositol
PubMed: 38893448
DOI: 10.3390/molecules29112572 -
European Journal of Medicinal Chemistry Jun 2024Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are... (Review)
Review
Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are often found in nature (e.g. alkaloids), the natural compounds of this group are rather rare as approved therapeutics. Thus, recently studied and approved azepane or azepine-congeners predominantly consist of semi-synthetically or synthetically-obtained scaffolds. In this review a comparison of approved drugs and recently investigated leads was proposed taking into regard their structural aspects (stereochemistry), biological activities, pharmacokinetic properties and confirmed molecular targets. The 7-membered N-heterocycles reveal a wide range of biological activities, not only against CNS diseases, but also as e.g. antibacterial, anticancer, antiviral, antiparasitic and against allergy agents. As most of the approved or investigated potential drugs or lead structures, belonging to 7-membered N-heterocycles, are synthetic scaffolds, this report also reveals different and efficient metal-free cascade approaches useful to synthesize both simple azepane or azepine-containing congeners and those of oligocyclic structures. Stereochemistry of azepane/azepine fused systems, in view of biological data and binding with the targets, is discussed. Apart from the approved drugs, we compare advances in SAR studies of 7-membered N-heterocycles (mainly from 2018 to 2023), whereas the related synthetic part concerning various domino strategies is focused on the last ten years.
PubMed: 38879971
DOI: 10.1016/j.ejmech.2024.116556 -
Chemosphere Aug 2024This study aims the characterization of several tianeptine transformation products in ultrapure water by simulated sunlight irradiation. Tianeptine was completely...
This study aims the characterization of several tianeptine transformation products in ultrapure water by simulated sunlight irradiation. Tianeptine was completely degraded after 106 h of exposition following pseudo-first-order kinetics (half-life time = 12.0 ± 2.4 h). Furthermore, an ultra-high-performance liquid chromatography coupled with a high-resolution quadrupole time-of-flight-mass spectrometry method was developed and fully validated taking into account different method performance parameters for the quantification of tianeptine in river water up to a concentration of 400 pg L. Following a non-targeted approach based on mass data-independent acquisition, eight different transformation products not previously reported in the literature were identified and accordingly elucidated, proposing a photodegradation mechanism based on the accurate tandem mass spectrometry information acquired. Irradiation experiments were replicated for a tianeptine solution prepared in a blank river water sample, resulting in the formation of the same transformation products and similar degradation kinetics. In addition, a toxicity assessment of the photoproducts was performed by in silico method, being generally all TPs of comparable toxicity to the precursor except for TP1, and showing a similar persistence in the environment except for TP2 and TP6, while TP4 was the only TP predicted as mutagenic. The developed method was applied for the analysis of four river water samples.
Topics: Water Pollutants, Chemical; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Photolysis; Thiazepines; Rivers; Kinetics; Sunlight
PubMed: 38849097
DOI: 10.1016/j.chemosphere.2024.142534 -
ESMO Open Jun 2024In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired...
BACKGROUND
In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control.
PATIENTS AND METHODS
Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant.
RESULTS
Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months.
CONCLUSIONS
PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.
Topics: Humans; Female; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Aged; Adult; Antineoplastic Combined Chemotherapy Protocols; Maximum Tolerated Dose; Oxazoles; Quinazolines; Paclitaxel; Uracil; Ado-Trastuzumab Emtansine; Fulvestrant; Trastuzumab; Imidazoles; Oxazepines; Antibodies, Monoclonal, Humanized
PubMed: 38833970
DOI: 10.1016/j.esmoop.2024.103465 -
Organic Letters Jun 2024Di(het)aryldiynes smoothly react with -benzylaldimines in a [4 + 3] cycloaddition manner under the action of the KOBu/DMSO system (60 °C, 30 min) to afford...
Di(het)aryldiynes smoothly react with -benzylaldimines in a [4 + 3] cycloaddition manner under the action of the KOBu/DMSO system (60 °C, 30 min) to afford pharmaceutically relevant tetra(het)arylsubstituted 3-azepines in up to 71% yield. The process involves the addition of azaallyl anions to one of the triple bonds of diynes followed by prototropic isomerization and cyclization of anionic intermediates with participation of the second triple bond. The cascade mechanism is consistent with quantum-chemical analysis (B2PLYP-D3/6-311+G**//B3LYP-D3/6-31+G* + PCM).
PubMed: 38819963
DOI: 10.1021/acs.orglett.4c01531 -
CPT: Pharmacometrics & Systems... Jun 2024Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in... (Randomized Controlled Trial)
Randomized Controlled Trial
Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.
Topics: Humans; Male; Electrocardiography; Adult; Female; Healthy Volunteers; Nasal Sprays; Heart Rate; Double-Blind Method; Young Adult; Dose-Response Relationship, Drug; Middle Aged; Azepines; Administration, Intranasal; Long QT Syndrome; Adolescent
PubMed: 38812357
DOI: 10.1002/psp4.13140 -
Phytomedicine : International Journal... Jul 2024Gastric cancer (GC) is difficult to treat with currently available treatments. Securinine (SCR) has a lengthy history of use in the treatment of disorders of the nervous...
BACKGROUND
Gastric cancer (GC) is difficult to treat with currently available treatments. Securinine (SCR) has a lengthy history of use in the treatment of disorders of the nervous system, and its anticancer potential has been gaining attention in recent years. The aim of this study was to explore the repressive effect of SCR on GC and its fundamental mechanism.
METHODS
The efficacy of SCR in GC cells was detected by MTT assays. Colony formation, flow cytometry and Transwell assays were used to assess the changes in the proliferation, apoptosis, cell cycle distribution, migration and invasion of GC cells after treatment. AGS (human gastric carcinoma cell)-derived xenografts were used to observe the effect of SCR on tumor growth in vivo. The molecular mechanism of action of SCR in GC was explored via RNA sequencing, bioinformatics analysis, Western blotting, molecular docking, and immunohistochemistry.
RESULTS
SCR was first discovered to inhibit the proliferation, migration, and invasion of GC cells while initiating apoptosis and cell cycle arrest in vitro. It was also established that SCR has excellent anticancer effects in vivo. Interestingly, AURKA acts as a crucial target of SCR, and AURKA expression can be blocked by SCR. Moreover, this study revealed that SCR suppresses the cell cycle and the β-catenin/Akt/STAT3 pathways, which were previously reported to be regulated by AURKA.
CONCLUSION
SCR exerts a notable anticancer effect on GC by targeting AURKA and blocking the cell cycle and β-catenin/Akt/STAT3 pathway. Thus, SCR is a promising pharmacological option for the treatment of GC.
Topics: Stomach Neoplasms; Humans; STAT3 Transcription Factor; Aurora Kinase A; Cell Line, Tumor; Animals; beta Catenin; Azepines; Proto-Oncogene Proteins c-akt; Heterocyclic Compounds, Bridged-Ring; Apoptosis; Cell Proliferation; Cell Movement; Mice, Nude; Dioxolanes; Mice, Inbred BALB C; Mice; Antineoplastic Agents, Phytogenic; Cell Cycle; Signal Transduction; Xenograft Model Antitumor Assays; Carcinogenesis; Molecular Docking Simulation; Lactones; Piperidines
PubMed: 38810557
DOI: 10.1016/j.phymed.2024.155735 -
Chemical Biology & Drug Design May 2024Evolutionary potential of viruses can result in outbreaks of well-known viruses and emergence of novel ones. Pharmacological methods of intervening the reproduction of...
Evolutionary potential of viruses can result in outbreaks of well-known viruses and emergence of novel ones. Pharmacological methods of intervening the reproduction of various less popular, but not less important viruses are not available, as well as the spectrum of antiviral activity for most known compounds. In the framework of chemical biology paradigm, characterization of antiviral activity spectrum of new compounds allows to extend the antiviral chemical space and provides new important structure-activity relationships for data-driven drug discovery. Here we present a primary assessment of antiviral activity of spiro-annulated derivatives of seven-membered heterocycles, oxepane and azepane, in phenotypic assays against viruses with different genomes, virion structures, and genome realization schemes: orthoflavivirus (tick-borne encephalitis virus, TBEV), enteroviruses (poliovirus, enterovirus A71, echovirus 30), adenovirus (human adenovirus C5), hantavirus (Puumala virus). Hit compounds inhibited reproduction of adenovirus C5, the only DNA virus in the studied set, in the yield reduction assay, and did not inhibit reproduction of RNA viruses.
Topics: Antiviral Agents; Humans; Spiro Compounds; Structure-Activity Relationship; Oxepins; Animals; Virus Replication; Phenotype
PubMed: 38789394
DOI: 10.1111/cbdd.14553