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Circulation Jan 2024Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy.
METHODS
Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379).
RESULTS
Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; <0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; =0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; =0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; =0.549).
CONCLUSIONS
Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.
Topics: Female; Humans; Male; Amlodipine; Coronary Artery Disease; Coronary Circulation; Cross-Over Studies; Microcirculation; Microvascular Angina; Myocardial Ischemia; Phenotype; Ranolazine; Middle Aged; Aged
PubMed: 37905403
DOI: 10.1161/CIRCULATIONAHA.123.066680 -
Pharmacological Research Aug 2023Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic... (Review)
Review
Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.
Topics: United States; Humans; Protein Kinase Inhibitors; Neoplasms; Protein Serine-Threonine Kinases; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Protein Kinases; Antineoplastic Agents
PubMed: 37454916
DOI: 10.1016/j.phrs.2023.106847 -
Redox Biology Jun 2024The oncogene Aurora kinase A (AURKA) has been implicated in various tumor, yet its role in meningioma remains unexplored. Recent studies have suggested a potential link...
The oncogene Aurora kinase A (AURKA) has been implicated in various tumor, yet its role in meningioma remains unexplored. Recent studies have suggested a potential link between AURKA and ferroptosis, although the underlying mechanisms are unclear. This study presented evidence of AURKA upregulation in high grade meningioma and its ability to enhance malignant characteristics. We identified AURKA as a suppressor of erastin-induced ferroptosis in meningioma. Mechanistically, AURKA directly interacted with and phosphorylated kelch-like ECH-associated protein 1 (KEAP1), thereby activating nuclear factor erythroid 2 related factor 2 (NFE2L2/NRF2) and target genes transcription. Additionally, forkhead box protein M1 (FOXM1) facilitated the transcription of AURKA. Suppression of AURKA, in conjunction with erastin, yields significant enhancements in the prognosis of a murine model of meningioma. Our study elucidates an unidentified mechanism by which AURKA governs ferroptosis, and strongly suggests that the combination of AURKA inhibition and ferroptosis-inducing agents could potentially provide therapeutic benefits for meningioma treatment.
Topics: Ferroptosis; Forkhead Box Protein M1; Aurora Kinase A; Humans; NF-E2-Related Factor 2; Animals; Mice; Meningioma; Piperazines; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Signal Transduction; Kelch-Like ECH-Associated Protein 1; Meningeal Neoplasms; Drug Resistance, Neoplasm
PubMed: 38642502
DOI: 10.1016/j.redox.2024.103137 -
Pathology Oncology Research : POR 2024The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with... (Review)
Review
The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins p21(ras); Proto-Oncogene Proteins; Adenocarcinoma of Lung; Mutation; Adenocarcinoma; ErbB Receptors; Acetonitriles; Piperazines; Pyrimidines
PubMed: 38605928
DOI: 10.3389/pore.2024.1611715 -
JAMA Network Open Dec 2023Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted.
OBJECTIVES
To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted.
DESIGN, SETTING, AND PARTICIPANTS
In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023.
INTERVENTIONS
Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone).
MAIN OUTCOMES AND MEASURES
Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components.
RESULTS
Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01651442.
Topics: Adult; Female; Humans; Middle Aged; Behavior Therapy; Fatigue; Sleep Initiation and Maintenance Disorders; Trazodone; Zolpidem; Male
PubMed: 38153735
DOI: 10.1001/jamanetworkopen.2023.49638 -
Biomaterials Oct 2023Lipid nanoparticles (LNPs) have shown great promise as delivery vehicles to transport messenger ribonucleic acid (mRNA) into cells and act as vaccines for infectious...
Lipid nanoparticles (LNPs) have shown great promise as delivery vehicles to transport messenger ribonucleic acid (mRNA) into cells and act as vaccines for infectious diseases including COVID-19 and influenza. The ionizable lipid incorporated within the LNP is known to be one of the main driving factors for potency and tolerability. Herein, we describe a novel family of ionizable lipids synthesized with a piperazine core derived from the HEPES Good buffer. These ionizable lipids have unique asymmetric tails and two dissimilar degradable moieties incorporated within the structure. Lipids tails of varying lengths, degrees of unsaturation, branching, and the inclusion of additional ester moieties were evaluated for protein expression. We observed several key lipid structure activity relationships that correlated with improved protein production in vivo, including lipid tails of 12 carbons on the ester side and the effect of carbon spacing on the disulfide arm of the lipids. Differences in LNP physical characteristics were observed for lipids containing an extra ester moiety. The LNP structure and lipid bilayer packing, visualized through Cryo-TEM, affected the amount of protein produced in vivo. In non-human primates, the Good HEPES LNPs formulated with an mRNA encoding an influenza hemagglutinin (HA) antigen successfully generated functional HA inhibition (HAI) antibody titers comparable to the industry standards MC3 and SM-102 LNPs, demonstrating their promise as a potential vaccine.
Topics: Animals; Humans; HEPES; Influenza, Human; COVID-19; Influenza Vaccines; Lipid Bilayers; Carbon; Esters; mRNA Vaccines
PubMed: 37480759
DOI: 10.1016/j.biomaterials.2023.122243 -
BMC Psychiatry Dec 2023This study included evaluation of the effectiveness of vortioxetine, a treatment for adults with major depressive disorder (MDD), using patient-reported outcome measures...
BACKGROUND
This study included evaluation of the effectiveness of vortioxetine, a treatment for adults with major depressive disorder (MDD), using patient-reported outcome measures (PROMs) in a real-world setting.
METHODS
This retrospective chart review analyzed the care experiences of adult patients with a diagnosis of MDD from Parkview Physicians Group - Mind-Body Medicine, Midwestern United States. Patients with a prescription for vortioxetine, an initial baseline visit, and ≥ 2 follow-up visits within 16 weeks from September 2014 to December 2018 were included. The primary outcome measure was effectiveness of vortioxetine on depression severity as assessed by change in Patient Health Questionnaire-9 (PHQ-9) scores ~ 12 weeks after initiation of vortioxetine. Secondary outcomes included changes in depression-related symptoms (i.e., sexual dysfunction, sleep disturbance, cognitive function, work/social function), clinical characteristics, response, remission, and medication persistence. Clinical narrative notes were also analyzed to examine sleep disturbance, sexual dysfunction, appetite, absenteeism, and presenteeism. All outcomes were examined at index (start of vortioxetine) and at ~ 12 weeks, and mean differences were analyzed using pairwise t tests.
RESULTS
A total of 1242 patients with MDD met inclusion criteria, and 63.9% of these patients had ≥ 3 psychiatric diagnoses and 65.9% were taking ≥ 3 medications. PHQ-9 mean scores decreased significantly from baseline to week 12 (14.15 ± 5.8 to 9.62 ± 6.03, respectively; p < 0.001). At week 12, the response and remission rates in all patients were 31.0% and 23.1%, respectively, and 67% continued vortioxetine treatment. Overall, results also showed significant improvements by week 12 in anxiety (p < 0.001), sexual dysfunction (p < 0.01), sleep disturbance (p < 0.01), cognitive function (p < 0.001), work/social functioning (p = 0.021), and appetite (p < 0.001). A significant decrease in presenteeism was observed at week 12 (p < 0.001); however, no significant change was observed in absenteeism (p = 0.466).
CONCLUSIONS
Using PROMs, our study results suggest that adults with MDD prescribed vortioxetine showed improvement in depressive symptoms in the context of a real-world clinical practice setting. These patients had multiple comorbid psychiatric and physical diagnoses and multiple previous antidepressant treatments had failed.
Topics: Adult; Humans; Vortioxetine; Depressive Disorder, Major; Retrospective Studies; Antidepressive Agents; Sexual Dysfunction, Physiological; Treatment Outcome; Double-Blind Method
PubMed: 38093196
DOI: 10.1186/s12888-023-05439-8 -
Vortioxetine - pharmacological properties and use in mood disorders. The current state of knowledge.Psychiatria Polska Dec 2023Vortioxetine is an antidepressant with a unique profile of receptor activity. The pharmacodynamic spectrum of vortioxetine activity is linked to the modulation of not... (Review)
Review
Vortioxetine is an antidepressant with a unique profile of receptor activity. The pharmacodynamic spectrum of vortioxetine activity is linked to the modulation of not only serotoninergic but also noradrenergic and dopaminergic transmission. At the same time, its pharmacokinetic properties determine good tolerance and safety, which are also observed in elderly patients and those burdened with somatic comorbidity. This work aims to sum up the knowledge coming from the most recent studies assessing the efficacy of vortioxetine. The efficacy of vortioxetine in the treatment of depression was confirmed in a large number of open studies, randomized controlled studies with placebo control, and meta-analyses thereof. What is more, the latest research shows that this drug allows depressed patients to achieve not only symptomatic remission but also an improvement of anhedonia and recovery in cognitive and occupational function. Furthermore, there are studies showing that vortioxetine is efficacious in the treatment of elderly patients, as well as subjects who have experienced trauma or suffer from bipolar depression. Vortioxetine is characterized by a good tolerance profile and safety; rarely does it cause severe adverse effects.
Topics: Aged; Humans; Antidepressive Agents; Mood Disorders; Treatment Outcome; Vortioxetine; Randomized Controlled Trials as Topic; Meta-Analysis as Topic
PubMed: 36571300
DOI: 10.12740/PP/OnlineFirst/151570 -
Nature Communications Jan 2024Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting...
Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph B-ALL patients. IL-17A promotes the progression of Ph B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph B-ALL progression and suggest potential therapeutic options for Ph B-ALL with Th17-enriched niches.
Topics: Humans; Imatinib Mesylate; Philadelphia Chromosome; Fusion Proteins, bcr-abl; Interleukin-17; Drug Resistance, Neoplasm; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Acute Disease
PubMed: 38172124
DOI: 10.1038/s41467-023-44270-3 -
ESC Heart Failure Oct 2023Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF.
METHODS AND RESULTS
The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters.
CONCLUSIONS
Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.
Topics: Humans; Male; Female; Aged; Heart Failure; Trimetazidine; Phosphocreatine; Cross-Over Studies; Stroke Volume; Adenosine Triphosphate
PubMed: 37530098
DOI: 10.1002/ehf2.14418