Результаты поиска

GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor.

1. The 5-HT4 receptor has only recently been identified but has yet to be cloned. This paper describes the pharmacology of a potent and selective 5-HT4 receptor antagonist, GR113808, which will be useful in the further characterization of this receptor. 2. On the guinea-pig ascending colon, GR113808 (1 nM-0.1 microM) behaved as an antagonist of 5-hydroxytryptamine (5-HT)-induced contraction, producing rightward displacements of the concentration-effect curve to 5-HT and a concentration-related depression of the maximum effect. However, the compound had no effect on cholecystokinin (CCK-8)-indu

Convulsive effects of systemic administration of the delta opioid agonist BW373U86 in mice.

A systemically active, nonpeptidic delta receptor-selective agonist, (+-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl) -3- hydroxybenzyl)-N,N-diethylbenzamide (BW373U86), produced a brief, nonlethal convulsion in mice. The behavioral pattern of convulsion produced by pentylenetetrazol was similar to that produced by systemic administration of BW373U86. Although several episodes of convulsion occurred with pentylenetetrazol, BWB373U86 produced a single, brief episode. Naltrexone (10.0 and 100 mg/kg) and naltrindole (1.0, 3.2 and 10.0 mg/kg), but not midazolam (0.32 mg/kg),

Differential inhibition by dopamine D-1 and D-2 antagonists of circling behaviour induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions.

The selective dopamine (DA) D-1 antagonist SCH 23390 antagonized the contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 in rats lesioned unilaterally with 6-hydroxy-DA but had a 600 times weaker effect against the preferential DA D-2 agonist pergolide. The D-2 antagonists clebopride and spiroperidol had the reverse selectivity. The mixed D-1/D-2 antagonists cis(Z)-flupentixol and cis(Z)-clopenthixol blocked the circling induced by either agonist. It is concluded that circling behaviour is mediated by closely related but independent DA D-1 and D-2 receptor sites.

Histone deacetylase inhibitors for leukemia treatment: current status and future directions.

Leukemia remains a major therapeutic challenge in clinical oncology. Despite significant advancements in treatment modalities, leukemia remains a significant cause of morbidity and mortality worldwide, as the current conventional therapies are accompanied by life-limiting adverse effects and a high risk of disease relapse. Histone deacetylase inhibitors have emerged as a promising group of antineoplastic agents due to their ability to modulate gene expression epigenetically. In this review, we explore these agents, their mechanisms of action, pharmacokinetics, safety and clinical efficacy, mon

Совпадение в полном тексте источника
… HDAC inhibitors can also be classified into structurally diverse classes, including hydroxamic acids (such as vorinostat and panobinostat), cyclic peptides (such as romidepsin), benzamides (such as entinostat), and short-chain fatty acids (such as valproic acid). … Chidamide Chidamide, also known as CS055/HBI-8000, is a novel benzamide class HDACi that has shown promising activity in preclinical models and clinical trials for the treatment of leukemia [ 76 , 77 ]. …

Interpreting clinical assays for histone deacetylase inhibitors.

As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all development steps. When "imprinted" early by the environment, epigenetic changes influence the organism at an early stage and can be transmitted to the progeny. Together with DNA sequence alterations, DNA aberrant cytosine methylation and microRNA deregulat

Structural optimization of AR and AR-V7 degraders incorporating silicon-based hydrophobic tags for treatment of castration-resistant prostate cancer.

Androgen receptor splice variant 7 (AR-V7) plays a crucial role in the malignant progression of castration-resistant prostate cancer (CRPC). Current research has demonstrated that the development of novel AR-V7 degraders holds broad prospects and is expected to serve as a clinical therapeutic regimen for this disease. In the present work, we utilized structural analogs of enzalutamide to conjugate a silicon-containing hydrophobic tag (SiHyT) moiety via Click chemistry, achieving the selective degradation of the androgen receptor (AR) and AR-V7. Mechanistic studies revealed that the degrader di

Effect of age and sex on cardiovascular outcomes among patients with chronic lymphocytic leukemia treated with Bruton tyrosine kinase inhibitors: a propensity matched analysis.

The combined effect of age and sex on the risk of atrial fibrillation (AF) in patients receiving Bruton tyrosine kinase inhibitors (BTKi) is unclear. To address this knowledge gap, propensity score matching was applied to the TriNetX database to generate matched cohorts of males and females with chronic lymphocytic leukemia (CLL) who received ibrutinib (n = 5312) or acalabrutinib (n = 3110). AF events during the first three years of BTKi therapy increased with age and were more common in males compared to females. For ibrutinib, nearly one in three males aged ≥75 developed AF compared with few

Anti-oxidative and anti-inflammatory effects of the phosphodiesterase 3/4 inhibitor ensifentrine.

Ensifentr ine is a dual PDE3/4 inhibitor that improves lung function and symptoms in COPD patients. Ensifentrine has anti-inflammatory effects, but these have not been studied in cells from COPD patients. Oxidative stress is increased in the lungs of COPD patients, but the potential for ensifentrine to modulate oxidative stress induced apoptosis has not been investigated. We investigated the effects of ensifentrine on inflammation and oxidative stress in cell models relevant to COPD. Peripheral blood mononuclear cells (PBMCs) from COPD patients and healthy controls and human bronchial epitheli

Inhibition of TrkB-BDNF positive feedback loop attenuates intervertebral disc degeneration and low back pain in a composite mouse model.

Intervertebral disc degeneration (IVDD) is a significant contributor to low back pain (LBP); however, the specific mechanisms involved remain unclear. Herein, a novel LBP mouse model was developed by integrating a bipedal standing model with a lumbar spine instability model (BS + LSI). This model effectively reproduced the behavioral characteristics of LBP and the pathological features of IVDD. Notably, a higher degree of degeneration and innervation in the endplates were observed in the BS + LSI mice. Transcriptome analysis revealed a significant upregulation of Ntrk2, the gene encoding TrkB,

ERK-mTOR crosstalk suppresses autophagy and upregulates proteasomal degradation pathway to confer chronic myeloid leukemia cells resistant to imatinib.

Drug resistance remains a critical barrier in effective cancer therapy. Previously, we demonstrated that expression of antiapoptotic protein (X-linked inhibitor of apoptosis protein [XIAP]), contributes to the development of TRAIL resistance in chronic myeloid leukemia (CML) cells. However, upon acquiring drug resistance (K562R and KCL22R), XIAP degradation shifted from the lysosomal to the proteasomal pathway. Consistently, XIAP expression was markedly elevated in tumor samples compared with normal controls and was significantly higher in patients with an imatinib failure (IMA-FL) than in the

Healthcare Resource Utilization and Costs in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia Treated With Covalent Bruton's Tyrosine Kinase Inhibitors: Real-World Impact of Cardiovascular Adverse Events.

INTRODUCTION: Although covalent Bruton's tyrosine kinase inhibitors (cBTKis) have transformed treatment of chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL), cBTKi-related cardiotoxicity is a known side effect. This real-world study evaluated incident cardiovascular adverse events (CVAE), healthcare resource utilization (HCRU), and costs among patients with CLL/SLL receiving cBTKis. METHODS: Adult patients with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020 and 2023 were identified using US claims data and followed up to 36 months post

Linperlisib Plus Chidamide in Relapsed or Refractory Cutaneous T-Cell Lymphoma: A Nonrandomized Clinical Trial.

IMPORTANCE: Patients with relapsed or refractory (r/r) cutaneous T-cell lymphoma (CTCL) have limited treatment options. Combining agents that target complementary oncogenic pathways may enhance efficacy while maintaining tolerability. OBJECTIVE: To evaluate the safety and efficacy of linperlisib, a PI3Kδ inhibitor, combined with chidamide, a histone deacetylase inhibitor, in patients with r/r CTCL. DESIGN, SETTING, AND PARTICIPANTS: This prospective, single-arm, phase 1 nonrandomized clinical trial with a 3 + 3 dose-escalation phase followed by dose expansion was conducted at a tertiary refe

N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis.

Stroke poses a significant risk of mortality, particularly among the elderly population. The pathophysiological process of ischemic stroke is complex, and it is crucial to elucidate its molecular mechanisms and explore potential protective drugs. Ferroptosis, a newly recognized form of programmed cell death distinct from necrosis, apoptosis, and autophagy, is closely associated with the pathophysiology of ischemic stroke. N6022, a selective inhibitor of S-nitrosoglutathione reductase (GSNOR), is a "first-in-class" drug for asthma with potential therapeutic applications. However, it remains unc

Development of new pyrazoles as class I HDAC inhibitors: Synthesis, molecular modeling, and biological characterization in leukemia cells.

Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, -2, and -3. Compounds 12b, 15b, and 15i were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC50 values of 0.93, 0.22, and 0.68 μM, respectively. The bes

PBPK Modeling of Entrectinib and Its Active Metabolite to Derive Dose Adjustments in Pediatric Populations Co-Administered with CYP3A4 Inhibitors.

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady-state systemic exposure on co-administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5-12.5 mg/kg and fluconazole at 3-12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-re

Neuroprotective effects of Lasmiditan and Sumatriptan in an experimental model of post-stroke seizure in mice: Higher effects with concurrent opioid receptors or KATP channels inhibitors.

BACKGROUND: Early post-stroke seizure frequently occurs in stroke survivors within the first few days and is associated with poor functional outcomes. Therefore, efficient treatments of such complications with less adverse effects are pivotal. In this study, we investigated the possible beneficial effects of lasmiditan and sumatriptan against post-stroke seizures in mice and explored underlying mechanisms in their effects. METHODS: Stroke was induced by double ligation of the right common carotid artery in mice. Immediately after the ligation, lasmiditan (0.1 mg/kg, intraperitoneally [i.p.])

Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia.

Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&Tag chromatin profiling for full automation, we identify common and tumor-subtype-specific sites of aberrant chromatin regulation induced by KMT2A oncofusion proteins. A subset of KMT2A onc

Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington's disease through inhibition of NF-κB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway.

Huntington's disease (HD) is a progressive neurodegenerative and hyperkinetic movement disorder. Decreased activity of cAMP-responsive element-binding protein (CREB) is thought to contribute to the death of striatal medium spiny neurons in HD. The present study has been designed to explore the possible role of roflumilast against qunilonic acid (QA) induced neurotoxicity in rats intending to investigate whether it inhibits the neuroinflammatory response through activation of the cAMP/CREB/BDNF signaling pathway. QA was microinjected (200 nmol/2 µl, bilaterally) through the intrastriatal route