Abstract:
:Flt3 is expressed by early myeloid and lymphoid progenitor cells and it regulates the proliferation and differentiation of hematopoietic cells. Flt3 is activated by the Flt3 ligand, the monomeric form of which is a polypeptide of about 200 amino acid residues. Both membrane-associated and soluble Flt3 ligands, which are a product of the same gene, function as noncovalent dimers. FLT3 mutations occur in about one-third of newly diagnosed acute myelogenous leukemia (AML) patients. This disease is a malignancy of hematopoietic progenitor cells with a variable clinical course; the incidence of this disorder is more than twice that of patients with chronic myelogenous leukemias (20,000 vs. 8500 new patients per year, respectively, in the United States). FLT3 internal tandem duplication (ITD) results from the head-to-tail duplication of from one to more than 100 amino acids within the juxtamembrane domain and such duplication occurs in about 20-25 % of patients with acute myelogenous leukemias. FLT3 tyrosine kinase (FLT3 TK) mutations, usually within the activation segment, occur in 5-10 % of these patients. The mainstay for the care of acute myelogenous leukemias include daunorubicin or idarubicin and cytarabine. Older patients who are not candidates for such traditional therapy are usually given 5-azacitidine, decitabine, or clofarabine. The addition of orally effective small molecule Flt3 inhibitors to these therapies may prolong event-free and overall survival, a subject of ongoing clinical studies. Midostaurin is US FDA-approved in combination with standard cytarabine and daunorubicin for first-line induction chemotherapy and in combination with cytarabine for second-line consolidation chemotherapy in the treatment of acute myelogenous leukemias with FLT3-postive mutations. Moreover, gilteritinib is a Flt3 multikinase inhibitor that is also FDA approved for the care of adult patients with relapsed or refractory acute myelogenous leukemias with FLT3 mutations. Quizartinib is a Flt3 multikinase inhibitor that was approved by the Ministry of Health, Labor and Welfare (MHLW) of Japan for the treatment of adult patients with relapsed/refractory Flt3-positive acute myelogenous leukemias. Gilteritinib and quizartinib bind to Flt3 with the inactive DFG-Dout structure and are classified as type II inhibitors. Furthermore, ponatinib is a multikinase inhibitor that is approved as therapy for Philadelphia chromosome-positive acute lymphoblastic and chronic myelogenous leukemias; it is used off label for the treatment of patients with acute myelogenous leukemias. Moreover, sorafenib is FDA-approved for the treatment of hepatocellular, renal cell, and differentiated thyroid cancers and it is used off label as maintenance therapy following allogeneic hematopoietic stem cell transplantation in the treatment of acute myelogenous leukemias. Other drugs that are in clinical trials for the treatment of this disorder include sunitinib, crenolanib, FF10101, and lestaurtinib. Unlike chronic myelogenous leukemias, which result solely from the formation of the BCR-Abl chimeric protein kinase, acute myelogenous leukemias result from multi-factorial causes and are prone to be resistant to both cytotoxic and targeted therapies. Consequently, there is a pressing need for better understanding the etiologies of acute myelogenous leukemias and for the development of more effective therapies.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Roskoski R Jrdoi
10.1016/j.phrs.2020.104725subject
Has Abstractpub_date
2020-05-01 00:00:00pages
104725eissn
1043-6618issn
1096-1186pii
S1043-6618(20)30659-9journal_volume
155pub_type
杂志文章,评审abstract::We studied here the effect of a wide range of adenosine concentration and time of preincubation, on the histamine release induced in the guinea pig mast cells by different stimulus. Adenosine (10(-5)-10(-3)m) potentiated the histamine release induced by antigen in the guinea pig heart (isolated and dispersed tissue) a...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1006/phrs.1999.0589
更新日期:2000-03-01 00:00:00
abstract::Kidney disease is a frequent complication in diabetes, and significant differences have been reported between male and female patients. Our working hypothesis was that diabetes might modify the vascular actions of testosterone in isolated rabbit renal arteries and the mechanisms involved in these actions. Testosterone...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2009.09.002
更新日期:2010-02-01 00:00:00
abstract::Iron is an essential element for virtually all organisms. It facilitates cell proliferation and growth but also contributes to major hallmarks of cancer such as tumor initiation, growth, and metastasis. Often, iron handling of tumor cells is disturbed, with altered iron acquisition, efflux, and storage. Targeting pert...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2017.03.018
更新日期:2017-06-01 00:00:00
abstract::A bovine dopamine transporter (bDAT) cDNA was transfected into CV-1 cells, a cell line that lacks vesicular storage and release mechanisms. Using this cell line, the effects of neuroleptic drugs on DAT-mediated uptake and release of dopamine (DA) were examined. All of the neuroleptic drugs tested, inhibited DA uptakes...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:
更新日期:1997-05-01 00:00:00
abstract::Proton pump inhibitors (PPIs) are used widely for the treatment of acid-related disorders. Despite their excellent efficacy and tolerance, the pharmacodynamics and pharmacokinetics of PPIs are affected by each patient's CYP2C19 and gastric H+,K+-ATPase genotype. The aim of this review was to analyze the effect of gene...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2019.104606
更新日期:2020-02-01 00:00:00
abstract::The effects of Nigella sativa (NS) on plasma lipid concentrations are controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to obtain a conclusive result in humans. PubMed-Medline, SCOPUS, Web of Science, and Google Scholar databases were searched (up to August 2015)...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2016.02.008
更新日期:2016-04-01 00:00:00
abstract::Metastatic cancers account for more than 90% of cancer mortality. The metastasis of all cancers is critically mediated by enzymes that degrade extracellular matrix. Aggressive tumors are characterized by an imbalance between enzymes that degrade ECM and endogenous inhibitors of the enzymes. Matrix metalloproteinases (...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2010.11.003
更新日期:2011-02-01 00:00:00
abstract::The effect of chloroquine and other antimalarial drugs on glutamate dehydrogenase activity was studied in liver and renal mitochondria as well as in kidney-cortex tubules of rabbit. In permeabilized mitochondria, with free access of substrates and drugs to glutamate dehydrogenase, 100 microns chloroquine decreased bot...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1006/phrs.1996.0108
更新日期:1997-01-01 00:00:00
abstract::An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physi...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2003.11.017
更新日期:2004-10-01 00:00:00
abstract::Alzheimer's is the neurodegenerative disease affecting the largest number of patients in the world. In spite of the intense research of the last decades, progress about its knowledge and therapy was limited. In particular, various cytotoxic processes remained debated, while the few drugs approved for therapy were of o...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2019.104316
更新日期:2019-08-01 00:00:00
abstract::Steroids (aldosterone and testosterone) and peptides of cerebral origin (angiotensin II and the tachykinins) control the salt intake of the rat. They arouse or suppress the behaviour and produce life-long enhancements of NaCl intake. Need-induced salt intake (salt appetite or salt hunger), which is the consequence of ...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/1043-6618(92)91380-y
更新日期:1992-02-01 00:00:00
abstract::Nebivolol, a third generation selective beta(1)-adrenoceptor (beta(1)-AR) antagonist, has been reported to reduce intracellular oxidative stress and to induce the release of nitric oxide (NO) from the endothelium. Nebivolol is also subjected to a complex metabolic process where glucuronidation, aromatic and alicyclic ...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2006.12.008
更新日期:2007-04-01 00:00:00
abstract::Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread worldwide through person-to-person contact, causing a public health emergency of international concern. At present, there is no specific antiviral treatment recommended for SARS-CoV-2 infection. Liu Shen capsule (LS), a traditional Chinese medicin...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2020.104850
更新日期:2020-08-01 00:00:00
abstract::This study was performed in order to investigate the cholinomimetic response of seminal vesicles isolated from rats treated with hydrocortisone acetate during perinatal life. At the adult phase, the body weight and the wet weight of the seminal vesicle of these animals were unchanged. However, these male rats exhibite...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:
更新日期:2003-07-01 00:00:00
abstract::Protein tyrosine phosphatases (PTPs), which are ubiquitously expressed in hematopoietic and non-hematopoietic cells, are critical for regulating cell proliferation as well as differentiation in the physiology of multicellular organisms. PTPs regulate the intracellular signaling mechanism of immune cells via dephosphor...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2019.04.011
更新日期:2019-06-01 00:00:00
abstract::Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been identified as baroreceptors. However, the underlying molecular mechanism for regulating these baroreceptors in hypertension remains unknown. In this study,...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2020.105391
更新日期:2020-12-19 00:00:00
abstract::The transparent bodies of see-through medaka fish has led to their use as models for in vivo cell and tissue imaging. However, these fish may also prove useful as models for pathological processes. Accumulating reports show that pathology in fish is similar to that in mammals, including humans. In this study, patholog...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2008.09.011
更新日期:2008-11-01 00:00:00
abstract::Male weanling Wistar rats were fed a 4% cholestyramine diet and used as a model to demonstrate that a reduction in serum low density lipoproteins stimulates de novo cholesterogenesis leading to DNA synthesis and cell proliferation. Feeding this diet resulted in a decrease in serum very low density lipoproteins and low...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/1043-6618(89)90195-3
更新日期:1989-09-01 00:00:00
abstract::Some bladder disorders, such as obstructive bladder and hyperactivity, may be caused partly by ischemia/reperfusion injury (I/R). The neuroprotective effects of estrogens were demonstrated in in vitro studies and a great interest in soy isoflavones (genistein and daidzein) as alternative to the synthetic estrogen rece...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2012.06.007
更新日期:2012-10-01 00:00:00
abstract::The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V(1a) and V(2) receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) i...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/s1043661802002062
更新日期:2002-11-01 00:00:00
abstract::We tested the efficacy of novel cyclooxygenase 2 (COX-2) inhibitors in counteracting glia-driven neuroinflammation induced by the amyloidogenic prion protein fragment PrP90-231 or lipopolysaccharide (LPS). In search for molecules with higher efficacy than celecoxib, we focused our study on its 2,3-diaryl-1,3-thiazolid...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2016.09.010
更新日期:2016-11-01 00:00:00
abstract::Moderate wine consumption has been shown to reduce cardiovascular (CV) risk, due to alcohol and polyphenolic compounds, such as resveratrol. We investigated the associations between total urinary resveratrol metabolites (TRMs) as biomarkers of wine and resveratrol consumption and CV risk factors in a large cross-secti...
journal_title:Pharmacological research
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/j.phrs.2012.03.009
更新日期:2012-06-01 00:00:00
abstract:OBJECTIVE:The vasorelaxant effect of 2-arachidonoylglycerol (2-AG) has been well characterised in animals. 2-AG is present in human vascular cells and is up-regulated in cardiovascular pathophysiology. However, the acute vascular actions of 2-AG have not been explored in humans. APPROACH:Mesenteric arteries were obtai...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2014.02.001
更新日期:2014-03-01 00:00:00
abstract::Gastrointestinal toxicity and red skin discoloration were the major side effects observed in leprosy patients undergoing long-term treatment with clofazimine (CFZ). Hematological and biochemical alterations have been cited among other side effects; however, their real magnitude and clinical significance at the doses c...
journal_title:Pharmacological research
pub_type: 临床试验,杂志文章
doi:10.1016/s1043-6618(02)00086-5
更新日期:2002-08-01 00:00:00
abstract::We aimed to investigate the cardiac changes in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with trastuzumab in an adjuvant setting. Two hundred and fifty-three women with HER2-positive breast cancer were included. The assessment of cardiovascular system and echocardiogr...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2013.10.001
更新日期:2013-12-01 00:00:00
abstract::Rats were treated with furosemide at intraperitoneal doses of 10, 20, and 30 mg kg(-1)day(-1)for 21 days, and some indices of thiamin status (liver, blood and urine thiamin concentrations, erythrocyte transketolase (TK) activity, and thiamin pyrophosphate (TPP) effect, which refers to the increase in TK activity in a ...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1006/phrs.1999.0632
更新日期:2000-07-01 00:00:00
abstract::Most cancer cells generate energy through aerobic glycolysis to enable their rapid growth and proliferation, which is a phenomenon known as Warburg effect. Inhibition of aerobic glycolysis reduces lactate and ATP generation in cancer cells, and ultimately kills tumor cells. Increasing evidence suggests that wogonin, a...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2018.07.011
更新日期:2018-09-01 00:00:00
abstract::Insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) have been proposed to be important mediators in cardioprotection. A large body of evidence indicates that insulin like growth factor-1 has pleotropic actions in the heart (i.e., contractility, metabolism, hypertrophy, autophagy, senescence and cell ...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2015.06.018
更新日期:2015-11-01 00:00:00
abstract::Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5-10 % depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ...
journal_title:Pharmacological research
pub_type: 杂志文章
doi:10.1016/j.phrs.2020.104960
更新日期:2020-09-01 00:00:00
abstract::Ranolazine has characteristic properties of a selective inhibitor of the inward sodium current. It is primarily indicated as an anti-anginal agent in patients with coronary artery disease and chronic stable angina. Recently, ranolazine has been noted to possibly impart beneficial effects in various other cardiac condi...
journal_title:Pharmacological research
pub_type: 杂志文章,评审
doi:10.1016/j.phrs.2015.10.018
更新日期:2016-01-01 00:00:00