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The Lancet. Oncology Oct 2023
Topics: Male; Humans; Abiraterone Acetate; Prostatic Neoplasms, Castration-Resistant; Phthalazines; Piperazines; Antineoplastic Combined Chemotherapy Protocols; Prednisone
PubMed: 37797626
DOI: 10.1016/S1470-2045(23)00448-5 -
Molecular Psychiatry Aug 2023Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology... (Review)
Review
Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.
Topics: Humans; Trimetazidine; Vasodilator Agents; Bipolar Disorder; Angina Pectoris; Antioxidants
PubMed: 37386057
DOI: 10.1038/s41380-023-02134-8 -
Breast (Edinburgh, Scotland) Aug 2023The optimal treatment following endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has not been established. We aimed to investigate treatment... (Observational Study)
Observational Study
PURPOSE
The optimal treatment following endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has not been established. We aimed to investigate treatment patterns and time to treatment failure (TTF) of subsequent therapy after palbociclib in a Japanese real-world setting.
METHDS
This retrospective observational study used de-identified data of patients with advanced breast cancer treated with palbociclib, using a nationwide claims database (April 2008 to June 2021). Measures included the type of subsequent therapies after palbociclib (endocrine-based therapy: ET alone, ET + CDK4/6i, and ET + mammalian target of rapamycin inhibitor [mTORi]; chemotherapy; chemotherapy + ET; and others) and their TTFs. The median TTF and 95% confidence interval (CI) were estimated using the Kaplan-Meier method.
RESULTS
Of 1170 patients treated with palbociclib, 224 and 235 received subsequent therapies after first- and second-line palbociclib treatment, respectively. Among them, 60.7% and 52.8% were treated with endocrine-based therapies as first subsequent therapy, including ET + CDK4/6i (31.2% and 29.8%, respectively). The median TTF (95% CI) of ET alone, ET + CDK4/6i, and ET + mTORi as first subsequent therapy after first-line palbociclib were 4.4 (2.8-13.7), 10.9 (6.5-15.6), and 6.1 (5.1-7.2) months, respectively. No apparent relationship between the treatment duration of prior ET + palbociclib and subsequent abemaciclib was observed.
CONCLUSION
This real-world study revealed that one-third of the patients received sequential CDK4/6i after ET + palbociclib, and treatment duration of ET + CDK4/6i following ET + palbociclib was the longest among the treatment options. Further data are awaited to determine whether ET + targeted therapy with CDK4/6i and mTORi provides acceptable treatment options following ET + palbociclib.
Topics: Humans; Female; Breast Neoplasms; Japan; Pyridines; Piperazines; Antineoplastic Combined Chemotherapy Protocols; Cyclin-Dependent Kinase 4; Protein Kinase Inhibitors; Receptor, ErbB-2
PubMed: 37267715
DOI: 10.1016/j.breast.2023.05.006 -
Developmental Cell Oct 2023Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a...
Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.
Topics: Animals; Mice; Humans; Cell Line, Tumor; Cell Differentiation; Tretinoin; Neuroblastoma; Adrenergic Agents; Piperazines; Pyridines
PubMed: 37734383
DOI: 10.1016/j.devcel.2023.08.028 -
Current Pharmaceutical Design 20242,5-Diketopiperazine (2,5-DKP) derivatives represent a family of secondary metabolites widely produced by bacteria, fungi, plants, animals, and marine organisms. Many... (Review)
Review
2,5-Diketopiperazine (2,5-DKP) derivatives represent a family of secondary metabolites widely produced by bacteria, fungi, plants, animals, and marine organisms. Many natural products with DKP scaffolds exhibited various pharmacological activities such as antiviral, antifungal, antibacterial, and antitumor. 2,5-DKPs are recognized as privileged structures in medicinal chemistry, and compounds that incorporate the 2,5-DKP scaffold have been extensively investigated for their anticancer properties. This review is a thorough update on the anti-cancer activity of natural and synthesized 2,5-DKPs from 1997 to 2022. We have explored various aspects of 2,5-DKPs modifications and summarized their structure-activity relationships (SARs) to gain insight into their anticancer activities. We have also highlighted the novel approaches to enhance the specificity and pharmacokinetics of 2,5-DKP-based anticancer agents.
Topics: Antineoplastic Agents; Diketopiperazines; Humans; Animals; Neoplasms; Structure-Activity Relationship; Molecular Structure; Biological Products; Cell Proliferation
PubMed: 38343054
DOI: 10.2174/0113816128291798240201112916 -
Pharmacological Research Feb 2024Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving...
Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5 mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p < 0.05). The mechanism through which Olaparib ameliorates ferroptosis in cardiac and leukocyte cells post-sepsis is attributed to its facilitation of mitophagy, thus favoring mitochondrial integrity. In conclusion, our findings suggest that low-dose Olaparib can improve mitochondrial quality by accelerating mitophagy flux, consequently inhibiting ferroptosis and preserving cardiac function after sepsis.
Topics: Humans; Mice; Animals; Mitophagy; Ferroptosis; Molecular Docking Simulation; Sepsis; Phosphatidate Phosphatase; Phthalazines; Piperazines
PubMed: 38228256
DOI: 10.1016/j.phrs.2023.107056 -
CNS Neuroscience & Therapeutics Oct 2023Parkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced...
AIM
Parkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced dyskinesia (LID), the most common complication of long-term L-dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non-dopaminergic systems contribute to LID development. As a 5-hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L-dopa administration and the potential mechanism of eltoprazine's amelioration of dyskinesia at the electrophysiological level in rats.
METHODS
Neural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta-gamma phase-amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity.
RESULTS
We detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta-gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic-corrected cortical beta power correlated robustly with aperiodic-corrected gamma power in M1. M1-DLS coherence and phase-locking values (PLVs) in the gamma band were enhanced following L-dopa administration. Eltoprazine intervention reduced gamma oscillations, theta-gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia.
CONCLUSION
Excessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma-band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.
Topics: Serotonin Receptor Agonists; Piperazines; Gamma Rhythm; Levodopa; Dyskinesia, Drug-Induced; Antiparkinson Agents; Animals; Rats; Disease Models, Animal; Motor Cortex
PubMed: 37122156
DOI: 10.1111/cns.14241 -
Journal of Pharmaceutical and... Jan 2024Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in...
Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in forensic toxicology. The detection of drugs in fingerprint samples can be used to show that an individual touching an item has consumed specific drugs. The aim of this study was to check the usefulness of fingerprints in drug analyses and detection of some analytes in this material. Fingerprint samples were collected on glass slides from a volunteer who consumed separately tablets containing pseudoephedrine, codeine, dextromethorphan, and used lidocaine spray. Moreover, fingerprints of individuals receiving sertraline, hydroxyzine and trazodone as part of their long-term treatment were analysed. The detection of drugs was conducted using the liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. After administration of single doses of drugs, they were detected up to 36 h (pseudoephedrine), 24 h (codeine), and less than 6 h (dextromethorphan and lidocaine) with maximum concentrations observed at 1-4 h. In fingerprints of a person who has finished treatment with hydroxyzine and sertraline it was possible to detect these drugs even 20 days after last drug administration. Cetirizine (hydroxyzine metabolite) and mCPP (trazodone metabolite) were determined in fingerprints of individuals under long-term treatment. This work has demonstrated that forensic toxicology can use fingerprints as alternative material. Drugs can be detected in fingerprints even after their single doses. Parent compounds predominate over metabolites in the fingerprints. The detection window depends on the type of drug and duration of the treatment.
Topics: Humans; Chromatography, Liquid; Trazodone; Tandem Mass Spectrometry; Dextromethorphan; Pseudoephedrine; Sertraline; Substance Abuse Detection; Pharmaceutical Preparations; Hydroxyzine; Codeine; Lidocaine
PubMed: 37926037
DOI: 10.1016/j.jpba.2023.115835 -
Journal of Medicinal Chemistry Jul 2023In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and...
In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, and , differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σRs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (, , and ) for further biological evaluation. Compound showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.
Topics: Humans; Histamine; Receptors, Histamine H3; Ligands; Nociception; Receptors, sigma; Piperazine; Piperidines; Neuralgia; Structure-Activity Relationship; Sigma-1 Receptor
PubMed: 37418295
DOI: 10.1021/acs.jmedchem.3c00430 -
Expert Review of Neurotherapeutics May 2024Major Depressive Disorder (MDD) is a mental health issue that significantly affects patients' quality of life and functioning. Despite available treatments, many... (Review)
Review
INTRODUCTION
Major Depressive Disorder (MDD) is a mental health issue that significantly affects patients' quality of life and functioning. Despite available treatments, many patients continue to suffer due to incomplete symptom resolution and side effects.
AREAS COVERED
This manuscript examines Vortioxetine's role in Major Depressive Disorder (MDD) treatment, highlighting its potential to reshape therapeutic strategies due to its unique Multimodal action and proven broad-spectrum efficacy in multiple depressive domains. A detailed examination of Vortioxetine's pharmacological aspects, including indications, dosage, pharmacodynamics, and pharmacokinetics, is provided, emphasizing its safety and effectiveness. The discussion extends to Vortioxetine's role in acute-phase treatment and maintenance of MDD and its profound impact on specialized depression domains.
EXPERT OPINION
Vortioxetine is distinguished for its novel multimodal serotonin modulation mechanism, showcasing significant promise as an innovative treatment for MDD. Its efficacy, which is dose-dependent, along with a commendable tolerability profile, positions it as a potential leading option for initial treatment strategies. The discourse on dosage titration, particularly the strategy of initiating treatment at lower doses followed by gradual escalation, underscores the approach toward minimizing initial adverse effects while optimizing therapeutic outcomes, aligning with the principles of personalized medicine in psychiatric care.
Topics: Antidepressive Agents; Anxiety; Cognitive Dysfunction; Depressive Disorder, Major; Emotions; Escitalopram; Post-Acute COVID-19 Syndrome; Precision Medicine; Selective Serotonin Reuptake Inhibitors; Serotonin; Vortioxetine; Humans; Neurotransmitter Agents; Animals
PubMed: 38536761
DOI: 10.1080/14737175.2024.2333394