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American Journal of Hematology Apr 2023
Randomized Controlled Trial
Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: Updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial.
Topics: Humans; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Leukemia, Myeloid, Acute
PubMed: 36655608
DOI: 10.1002/ajh.26847 -
International Journal of Molecular... Oct 2021Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of...
Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of Ate. Male Sprague Dawley (SD) rats were fed a high-fat diet for seven months and used as a hyperlipidemia model. The lipid level and liver function of the hyperlipidemia rats were studied by the levels of TG, TC, LDL, HDL, ALT, and AST in serum after intragastric administration with different doses of Ate. HE staining was used to observe the pathological changes of the rat liver and gastrocnemius muscle. The lipid deposits in the liver of rats were observed by staining with ORO. The genes in the rat liver were sequenced by RNA-sequencing. The results of the RNA-sequencing were further examined by qRT-PCR and western blotting. Biochemical test results indicated that Ate could obviously improve the metabolic disorder and reduce both the ALT and AST levels in serum of the hyperlipidemia rats. Pathological results showed that Ate could improve HFD-induced lipid deposition and had no muscle toxicity. The RNA-sequencing results suggested that Ate affected liver lipid metabolism and cholesterol, metabolism in the hyperlipidemia-model rats may vary via the PPAR-signaling pathway. The western blotting and qRT-PCR results demonstrated the Ate-regulated lipid metabolism in the hyperlipidemia model through the PPAR-signaling pathway and HMGCR expression. In brief, Ate can significantly regulate the blood lipid level of the model rats, which may be achieved by regulating the PPAR-signaling pathway and HMGCR gene expression.
Topics: Animals; Anticholesteremic Agents; Atorvastatin; Body Weight; Diet, High-Fat; Gene Expression Regulation; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipid Metabolism; Liver; Male; PPAR gamma; Rats, Sprague-Dawley; Signal Transduction; Rats
PubMed: 34681767
DOI: 10.3390/ijms222011107 -
Journal of the American College of... Oct 2021
Topics: Anticholesteremic Agents; Ezetimibe; Humans
PubMed: 34620407
DOI: 10.1016/j.jacc.2021.08.029 -
Chemistry (Weinheim An Der Bergstrasse,... Dec 2020The recently delineated structure- and reactivity-based concept of antivitamins B has begun to bear fruit by the generation, and study, of a range of such B -dummies,... (Review)
Review
The recently delineated structure- and reactivity-based concept of antivitamins B has begun to bear fruit by the generation, and study, of a range of such B -dummies, either vitamin B -derived, or transition metal analogues that also represent potential antivitamins B or specific B -antimetabolites. As reviewed here, this has opened up new research avenues in organometallic B -chemistry and bioinorganic coordination chemistry. Exploratory studies with antivitamins B have, furthermore, revealed some of their potential, as pharmacologically interesting compounds, for inducing B -deficiency in a range of organisms, from hospital resistant bacteria to laboratory mice. The derived capacity of antivitamins B to induce functional B -deficiency in mammalian cells and organs also suggest their valuable potential as growth inhibitors of cancerous human and animal cells.
Topics: Animals; Antimetabolites; Humans; Neoplasms; Vitamin B 12; Vitamins
PubMed: 32956545
DOI: 10.1002/chem.202003788 -
Current Atherosclerosis Reports Mar 2024Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide... (Review)
Review
PURPOSE OF REVIEW
Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications.
RECENT FINDINGS
Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20-30% as monotherapy and by 40-50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20-30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid-treated patients. Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Fatty Acids; Dicarboxylic Acids
PubMed: 38294660
DOI: 10.1007/s11883-024-01188-5 -
Medicina (Kaunas, Lithuania) Apr 2023Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of... (Review)
Review
Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of coronary artery disease and peripheral vascular disease, including stroke. Recent guidelines recommend considering low-density lipoprotein cholesterol (LDL-C)-lowering therapies, such as statins (preferably), ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to prevent the occurrence or recurrence of stroke, adhering to the "lower is better" approach. In this review, we examined the evidence supporting lipid-lowering medications like statins, ezetimibe, and PCSK9 inhibitors for secondary stroke prevention and dyslipidemia management in different stroke subtypes. Stroke guidelines advocate for administering the maximum tolerable dose of statins as the primary treatment and as soon as possible despite the potential for new-onset diabetes mellitus and possible muscle and liver toxicity due to their demonstrated benefits in secondary prevention of cardiovascular diseases and mortality reduction. When statin use is insufficient for LDL lowering, ezetimibe and PCSK9 inhibitors are recommended as complementary therapies. It is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Proprotein Convertase 9; PCSK9 Inhibitors; Ezetimibe; Cardiovascular Diseases; Dyslipidemias; Cholesterol, LDL; Stroke; Secondary Prevention
PubMed: 37109734
DOI: 10.3390/medicina59040776 -
American Journal of Cardiovascular... May 2022Despite the availability of lipid-lowering therapies (LLTs) that are safe and effective, the overall rate of low-density lipoprotein cholesterol (LDL-C) control at a... (Review)
Review
Despite the availability of lipid-lowering therapies (LLTs) that are safe and effective, the overall rate of low-density lipoprotein cholesterol (LDL-C) control at a population level in real-life studies is low. Higher-intensity treatment, earlier intervention, and longer-term treatment have all been shown to improve outcomes. However, in clinical practice, actual exposure to LLT is a product of the duration and intensity of, and adherence to, the treatment. To increase exposure to LLTs, the European Society of Cardiology guidelines recommended a stepwise optimization of LLTs by increasing statin intensity to the maximally tolerated dose, with subsequent addition of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Evidence from randomized controlled trials performed in a range of patients suggested that adding ezetimibe to statins rather than doubling the statin dose resulted in significantly more patients at LDL-C goal and significantly fewer patients discontinuing treatment because of adverse events. In addition, data showed that combination treatments effectively increased exposure to LLT. Despite these data and recommendations, optimization of LLT is often limited to increasing statin dose. Therapeutic inertia and poor treatment adherence are significant and prevalent barriers to increasing treatment exposure. They are known to be influenced by pill burden and complexity of treatment. Single-pill combinations provide a strategic approach that supports the intensification of treatment without increasing pill burden or treatment complexity. Single-pill combinations, compared with free associations, have been shown to increase the adherence to LLT and the percentage of patients at LDL-C goal.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Dyslipidemias; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9
PubMed: 34549371
DOI: 10.1007/s40256-021-00498-2 -
JAMA Nov 2019
Topics: Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 31714973
DOI: 10.1001/jama.2019.16598 -
Translational Psychiatry Apr 2023Observational studies and randomized controlled trials presented inconsistent findings on the effects of cholesterol-lowering statins on depression. It therefore remains...
Observational studies and randomized controlled trials presented inconsistent findings on the effects of cholesterol-lowering statins on depression. It therefore remains unclear whether statins have any beneficial effects on depression, and if so, what the underlying molecular mechanisms are. Here, we aimed to use genomic approaches to investigate this further. Using Connectivity Map (CMap), we first investigated whether statins and antidepressants shared pharmacological effects by interrogating gene expression responses to drug exposure in human cell lines. Second, using Mendelian randomization analysis, we investigated both on-target (through HMGCR inhibition) and potential off-target (through ITGAL and HDAC2 inhibition) causal effects of statins on depression risk and depressive symptoms, and traits related to the shared biological pathways identified from CMap analysis. Compounds inducing highly similar gene expression responses to statins in HA1E cells (indicated by an average connectivity score with statins > 90) were found to be enriched for antidepressants (12 out of 38 antidepressants; p = 9E-08). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for diverse cellular and metabolic pathways, and various immune activation, development and response processes. MR analysis did not identify any significant associations between statin exposure and depression risk or symptoms after multiple testing correction. However, genetically proxied HMGCR inhibition was strongly associated with alterations in platelets (a prominent serotonin reservoir) and monocyte percentage, which have previously been implicated in depression. Genetically proxied ITGAL inhibition was strongly associated with basophil, monocyte and neutrophil counts. We identified biological pathways that are commonly perturbed by both statins and antidepressants, and haematological biomarkers genetically associated with statin targets. Our findings warrant pre-clinical investigation of the causal role of these shared pathways in depression and potential as therapeutic targets, and investigation of whether blood biomarkers may be important considerations in clinical trials investigating effects of statins on depression.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Transcriptome; Mendelian Randomization Analysis; Gene Expression Profiling
PubMed: 37015906
DOI: 10.1038/s41398-023-02403-8 -
Molecules (Basel, Switzerland) Jun 2022, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT),...
, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target . We found that CHT/ERGT inhibited cell growth in vitro, yielding EC values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with , doubling their survival time following daily treatment for 8-10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development.
Topics: Animals; Antimetabolites; Ergosterol; Humans; Mice; Steroids; Sterols; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 35807334
DOI: 10.3390/molecules27134088