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Bexarotene

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https://www.readbyqxmd.com/read/28205585/neuronally-directed-effects-of-rxr-activation-in-a-mouse-model-of-alzheimer-s-disease
#1
M M Mariani, T Malm, R Lamb, T R Jay, L Neilson, B Casali, L Medarametla, G E Landreth
Alzheimer's disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28169169/drugbank-screening-revealed-alitretinoin-and-bexarotene-as-liver-x-receptor-modulators
#2
Pascal Heitel, Janosch Achenbach, Daniel Moser, Ewgenij Proschak, Daniel Merk
In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development...
January 25, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28167509/results-from-a-phase-i-ii-open-label-dose-finding-study-of-pralatrexate-and-oral-bexarotene-in-patients-with-relapsed-refractory-cutaneous-t-cell-lymphoma
#3
Madeleine Duvic, Youn H Kim, Pier Luigi Zinzani, Steven Horwitz
PURPOSE: Pralatrexate is a folic acid analog metabolic inhibitor similar to methotrexate,that has shown tolerability and efficacy with an overall response rate of 45% in a phase 1 dose de-escalation study of patients with relapsed/refractory cutaneous T-cell lymphoma CTCL. EXPERIMENTAL DESIGN: The object of this phase I/II open-label, multi-center clinical trial was to determine the maximum tolerated dose (MTD) and recommended dose of pralatrexate plus oral bexarotene in 34 patients with relapsed/refractory CTCL who had failed prior systemic therapies...
February 6, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28119332/brentuximab-beats-standard-therapies-for-ctcl
#4
(no author information available yet)
Compared with a physician's choice of either methotrexate or bexarotene, the CD30-directed antibody-drug conjugate brentuximab vedotin led to significantly superior clinical responses in patients with cutaneous T-cell lymphomas, according to the results of the international phase III ALCANZA trial.
January 24, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28099842/brown-adipogenic-reprogramming-induced-by-a-small-molecule
#5
Baoming Nie, Tao Nie, Xiaoyan Hui, Ping Gu, Liufeng Mao, Kuai Li, Ran Yuan, Jiashun Zheng, Haixia Wang, Ke Li, Shibing Tang, Yu Zhang, Tao Xu, Aimin Xu, Donghai Wu, Sheng Ding
Brown adipose tissue (BAT) has attracted considerable research interest because of its therapeutic potential to treat obesity and associated metabolic diseases. Augmentation of brown fat mass and/or its function may represent an attractive strategy to enhance energy expenditure. Using high-throughput phenotypic screening to induce brown adipocyte reprogramming in committed myoblasts, we identified a retinoid X receptor (RXR) agonist, bexarotene (Bex), that efficiently converted myoblasts into brown adipocyte-like cells...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28088372/nanoformulation-of-dual-bexarotene-tailed-phospholipid-conjugate-with-high-drug-loading
#6
Ruiyu He, Yawei Du, Longbing Ling, Muhammad Ismail, Yongpeng Hou, Chen Yao, Xinsong Li
Bexarotene (Bex), a synthetic retinoid X receptor-selective activator, has been proved to be an efficacious chemotherapeutic agent. But, its clinical application is limited due to the poor solubility. In this report, dual bexarotene-tailed phospholipid (DBTP) conjugate based nanovesicles were prepared in order to develop new nanoformulation. DBTP conjugate was first synthesized by conjugating two Bex molecules with glycerophosphorylcholine (GPC) through facial esterification. The amphiphilic DBTP nanovesicles were prepared without any additive by reverse-phase evaporation method...
January 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27978471/simple-and-sensitive-hplc-uv-method-for-determination-of-bexarotene-in-rat-plasma
#7
Jong Bong Lee, Atheer Zgair, Tae Hwan Kim, Min Gi Kim, Sun Dong Yoo, Peter M Fischer, Pavel Gershkovich
Bexarotene is currently marketed for treatment of cutaneous T-cell lymphoma and there has been growing interest in its therapeutic effectiveness for other cancers. Neuroprotective effects of bexarotene have also been reported. In this study, a simple, sensitive and cost-efficient bioanalytical method for determination of bexarotene in rat plasma was developed and fully validated. The method utilises protein precipitation with acetonitrile and liquid-liquid extraction with n-hexane-ethyl acetate (10:1, v/v)...
January 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27865806/ikaros-exploiting-and-targeting-the-hematopoietic-stem-cell-niche-in%C3%A2-b-progenitor-acute-lymphoblastic-leukemia
#8
REVIEW
Michelle L Churchman, Charles G Mullighan
Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high-risk B-progenitor acute lymphoblastic leukemia (ALL), such as BCR-ABL1-positive (Ph+) and Ph-like ALL, and are associated with poor outcome even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiation, skewing lineage of leukemia from myeloid to lymphoid, and, in Ph+ leukemia, conferring resistance to tyrosine kinase inhibitor (TKI) therapy without abrogating ABL1 inhibition...
February 2017: Experimental Hematology
https://www.readbyqxmd.com/read/27842487/molecular-interactions-of-bexarotene-a-retinoid-drug-and-alzheimer-s-a%C3%AE-peptide-a-docking-study
#9
Zeenat Mirza, Mohd Amin Beg
Alzheimer's disease (AD) pathogenesis is primarily hallmarked by the production and accumulation of amyloid beta (Aβ) peptide. Along with the understanding of the neurodegenerative disease progression and its pathophysiological mechanisms, development of anti-Aβ targeted effective therapeutics is essential for AD management. Numerous therapeutic approaches targeting the production, toxicity and removal of Aβ are being attempted worldwide. Prime need is to design inhibitors which can slow down the Aβ aggregation process in a physiological environment...
November 14, 2016: Current Alzheimer Research
https://www.readbyqxmd.com/read/27833522/histamine-h3-receptors-and-its-antagonism-as-a-novel-mechanism-for-antipsychotic-effect-a-current-preclinical-clinical-perspective
#10
REVIEW
Danish Mahmood
Histamine H3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia...
October 2016: International Journal of Health Sciences
https://www.readbyqxmd.com/read/27734691/-endocrine-complications-of-modern-cancer-therapy
#11
Jan Čáp
Treatment with tyrosine kinase inhibitors leads to thyroid dysfunction in up to one half of treated patients, hypothyroidism being the most common. It is caused by destructive thyroiditis, impaired transport of T4 into the cell and deiodinase induction. Bexarotene is a nuclear retinoid X receptor agonist. Its application is accompanied with central hypothyroidism and hypertriglyceriaemia in virtually all patients and it also increases thyroxin metabolism. Autoimmune endocrine side effects are common in cancer immunotherapy...
2016: Vnitr̆ní Lékar̆ství
https://www.readbyqxmd.com/read/27714239/tetrazolone-as-an-acid-bioisostere-application-to-marketed-drugs-containing-a-carboxylic-acid
#12
Matthew A J Duncton, Ryan B Murray, Gary Park, Rajinder Singh
Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid. Compound 7, a tetrazolone of the anti-hypertensive drug, telmisartan 6, was shown to be a potent AT1 antagonist (Kb = 0.14 nM), with activity comparable to telmisartan itself (Kb = 0.44 nM). Additionally, compound 9, a tetrazolone congener of the marketed anti-cancer agent, bexarotene 8, was shown to be an agonist at the retinoid X receptor alpha (EC50 = 64 nM). Compounds containing a tetrazolone group showed similar microsomal stability and plasma protein binding to marketed acid counterparts, while also reducing the value for clog P...
October 4, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27714179/a-one-pot-synthesis-of-tetrazolones-from-acid-chlorides-understanding-functional-group-compatibility-and-application-to-the-late-stage-functionalization-of-marketed-drugs
#13
Matthew A J Duncton, Rajinder Singh
A one-pot and scalable synthesis of tetrazolones (tetrazol-5-ones) from acid chlorides using azidotrimethylsilane is presented. The reaction tolerates many functional groups and can furnish aryl-, heteroaryl-, alkenyl-, or alkyl-substituted tetrazolone products in moderate to excellent yield (14-94%). No reduction in yield was observed when the reaction was undertaken on a larger-scale (20-36 g). The method could be used for the late-stage functionalization of pharmaceuticals, to provide tetrazolone congeners of the marketed drugs aspirin, indomethacin, probenecid, telmisartan, bexarotene, niacin (vitamin B3), and the active metabolite of the recently-launched immuno-modulatory agent, BG-12 (Tecfidera(®))...
October 4, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27624652/bexarotene-targets-autophagy-and-is-protective-against-thromboembolic-stroke-in-aged-mice-with-tauopathy
#14
Mikko T Huuskonen, Sanna Loppi, Hiramani Dhungana, Velta Keksa-Goldsteine, Sighild Lemarchant, Paula Korhonen, Sara Wojciechowski, Eveliina Pollari, Piia Valonen, Juho Koponen, Akihiko Takashima, Gary Landreth, Gundars Goldsteins, Tarja Malm, Jari Koistinaho, Katja M Kanninen
Stroke is a highly debilitating, often fatal disorder for which current therapies are suitable for only a minor fraction of patients. Discovery of novel, effective therapies is hampered by the fact that advanced age, primary age-related tauopathy or comorbidities typical to several types of dementing diseases are usually not taken into account in preclinical studies, which predominantly use young, healthy rodents. Here we investigated for the first time the neuroprotective potential of bexarotene, an FDA-approved agent, in a co-morbidity model of stroke that combines high age and tauopathy with thromboembolic cerebral ischemia...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27619199/differentiation-therapy-in-poor-risk-myeloid-malignancies-results-of-companion-phase-ii-studies
#15
Kelly J Norsworthy, Eunpi Cho, Jyoti Arora, Jeanne Kowalski, Hua-Ling Tsai, Erica Warlick, Margaret Showel, Keith W Pratz, Lesley A Sutherland, Steven D Gore, Anna Ferguson, Sarah Sakoian, Jackie Greer, Igor Espinoza-Delgado, Richard J Jones, William H Matsui, B Douglas Smith
Pre-clinical data in non-M3 AML supports the use of differentiation therapy, but clinical activity has been limited. Myeloid growth factors can enhance anti-leukemic activity of differentiating agents in vitro. We conducted companion phase II trials investigating sargramostim (GM-CSF) 125μg/m(2)/day plus 1) bexarotene (BEX) 300mg/m(2)/day or 2) entinostat (ENT) 4-8mg/m(2)/week in patients with MDS or relapsed/refractory AML. Primary endpoints were response after at least two treatment cycles and toxicity. 26 patients enrolled on the BEX trial had a median of 2 prior treatments and 24 enrolled on the ENT trial had a median of 1...
October 2016: Leukemia Research
https://www.readbyqxmd.com/read/27592633/modeling-synthesis-and-biological-evaluation-of-potential-retinoid-x-receptor-rxr-selective-agonists-analogues-of-4-1-3-5-5-8-8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl-ethynyl-benzoic-acid-bexarotene-and-6-ethyl-5-5-8-8-tetrahydronaphthalen-2-yl-amino-nicotinic
#16
Michael C Heck, Carl E Wagner, Pritika H Shahani, Mairi MacNeill, Aleksandra Grozic, Tamana Darwaiz, Micah Shimabuku, David G Deans, Nathan M Robinson, Samer H Salama, Joseph W Ziller, Ning Ma, Arjan van der Vaart, Pamela A Marshall, Peter W Jurutka
Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments...
October 13, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27588517/morphology-in-vivo-distribution-and-antitumor-activity-of-bexarotene-nanocrystals-in-lung-cancer
#17
Yongjie Wang, Jinghong Rong, Jiaozhen Zhang, Yu Liu, Xuelian Meng, Hejian Guo, Hongsheng Liu, Lijiang Chen
The objective of this study was to develop and evaluate the morphology, biodistribution and antitumor activity of bexarotene nanocrystals delivery system. The morphology was investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscope and bexarotene nanocrystals exhibited the advantages of making the efficacy more steady and durable compared with control group in lung with less cardiac accumulation as shown by biodistribution studies in vivo. In addition, MTT assay, flow cytometry analysis, observation of morphological changes and apoptotic body demonstrated that bexarotene nanocrystals could significantly enhance the in vitro cytotoxicity and induced G1 cycle arrest and apoptosis against A549 cells...
September 2, 2016: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/27567858/abca1-agonist-reverses-the-apoe4-driven-cognitive-and-brain-pathologies
#18
Anat Boehm-Cagan, Roni Bar, Ori Liraz, John K Bielicki, Jan O Johansson, Daniel M Michaelson
The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits...
October 4, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27553293/preclinical-pet-neuroimaging-of-11c-bexarotene
#19
Benjamin H Rotstein, Michael S Placzek, Hema S Krishnan, Aleksandra Pekošak, Thomas Lee Collier, Changning Wang, Steven H Liang, Ethan S Burstein, Jacob M Hooker, Neil Vasdev
Activation of retinoid X receptors (RXRs) has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [(11)C]CO2 fixation and preliminary positron emission tomography (PET) neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [(11)C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions...
2016: Molecular Imaging
https://www.readbyqxmd.com/read/27546732/cd8-mycosis-fungoides-clinically-masquerading-as-alopecia-areata
#20
Sapna M Amin, Timothy Tan, Joan Guitart, Maria Colavincenzo, Pedram Gerami, Pedram Yazdan
A 33-year-old female with a 7-year history of CD8-positive hypopigmented mycosis fungoides (MF) involving the trunk and extremities presented with a large well-defined alopecic patch on her frontal scalp. Clinically, this area resembled alopecia areata (AA) and was without hypopigmentation or erythema. A scalp biopsy revealed a non-scarring inflammatory alopecia and a superficial band-like atypical lymphoid infiltrate with prominent epidermotropism. Atypical, predominately CD8-positive lymphocytes were seen surrounding and infiltrating the bulb portion of several hair follicles...
December 2016: Journal of Cutaneous Pathology
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