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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
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
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
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
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
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
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
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
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
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...
August 22, 2016: Journal of Cutaneous Pathology
Toshihisa Hamada, Makoto Sugaya, Yoshiki Tokura, Mikio Ohtsuka, Ryoji Tsuboi, Tetsuo Nagatani, Mamori Tani, Mitsuru Setoyama, Shigeto Matsushita, Kazuhiro Kawai, Kentaro Yonekura, Tsuyoshi Yoshida, Toshiaki Saida, Keiji Iwatsuki
Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)-selective retinoid, were evaluated in Japanese patients with stage IIB-IVB and relapsed/refractory stage IB-IIA cutaneous T-cell lymphomas (CTCL). This study was conducted as a multicenter, open-label, historically controlled, single-arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m(2) for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m(2) in three patients...
August 20, 2016: Journal of Dermatology
L M Lin, F Peng, Y P Liu, D J Chai, R B Ning, C S Xu, J X Lin
BACKGROUND AND AIMS: Diabetes contributes to atherosclerosis partially through induction of oxidative stress. Both vitamin D receptor (VDR) and retinoid X receptor (RXR) agonists exhibit anti-atherogenic effects. METHODS: We explored the effects of combination treatment with VDR and RXR agonists (represented by calcitriol and bexarotene, respectively) on atherosclerosis progression and the mechanisms involved, using a diabetes model of mice. The animals were intragastrically fed calcitriol (200 ng/kg, twice-a-week), bexarotene (10 mg/kg, once-daily) either alone or in combination for 12 weeks...
August 2016: Atherosclerosis
William T Johnson, Rebecca J Leeman-Neill, Parth Patel, Jonhan Ho, Lisa M Grandinetti, Jaroslaw Jedrych, Fiona E Craig
A 77-year-old white male presented to the clinic with two isolated cutaneous tumors on his forehead. A cutaneous biopsy showed a focally folliculotropic CD4 cutaneous lymphoma. The tumors were irradiated with a complete response, and he was started on oral bexarotene. He experienced localized cutaneous relapse 3 months into treatment. These new tumors now revealed a surprisingly CD8 cytotoxic phenotype, but with the same clone. A systemic workup was negative. His regimen was switched to romidepsin, and he was treated with local radiation again...
June 13, 2016: American Journal of Dermatopathology
Marta Domínguez, Susana Alvarez, Angel R de Lera
Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. Through these liaisons RXR ligands ("rexinoids") either transcriptionally activate on their own the "permissive" subclass of heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) or synergize with partner ligands in the "non-permissive" subclass of heterodimers (RAR/RXR, VDR/RXR and TR/RXR). The nature and extent of the interaction of the ligand-receptor complexes with co-regulators, which is cell and context-dependent, results ultimately in transcriptional modulation of cognate gene networks...
June 16, 2016: Current Topics in Medicinal Chemistry
Karen T Liby, Michael B Sporn
Rexinoids are selective ligands for the nuclear receptors known as RXRs. They do not bind to the receptors for all-trans-retinoic acid (RARs). Many new rexinoids have been synthesized and then assayed for their ability to suppress proliferation of cancer cells, to inhibit activation of inflammatory cells of the tumor microenvironment, and to prevent carcinogenesis in animal models relevant to human disease. Here we review the literature on the effects of 4 such rexinoids: bexarotene, LG100268, LG101506, and NRX194204...
June 16, 2016: Current Topics in Medicinal Chemistry
Kevin P Koster, Conor Smith, Ana C Valencia-Olvera, Gregory R J Thatcher, Leon M Tai, Mary Jo LaDu
Alzheimer disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques, composed of amyloid-beta peptide (Aβ) and neurofibrillary tangles, composed of aberrantly phosphorylated tau. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 12-fold with a double allele compared to APOE3. In contrast, APOE2 reduces AD risk ~2-fold per allele. Accumulating evidence demonstrates that apolipoprotein E4 (apoE4) plays a multifactorial role in AD pathogenesis, although the exact mechanisms remain unclear...
June 16, 2016: Current Topics in Medicinal Chemistry
Roberto Collado-Borrell, Vicente Escudero-Vilaplana, Rosa Romero-Jiménez, Irene Iglesias-Peinado, Ana Herranz-Alonso, María Sanjurjo-Sáez
OBJECTIVE: To review interactions between oral antineoplastic agents (OAAs) for the treatment of solid and hematological tumors and common food and medicinal plants. MATERIALS AND METHODS: All potential interactions between OAAs, medicinal plants and food were reviewed. OAAs were considered to be drugs for oral administration that have direct antitumor activity and were approved by the European Medicines Agency in April 2015. We performed the literature search in Pubmed(®) considering only medicinal plants and food...
November 2016: Journal of Cancer Research and Clinical Oncology
Patricia M Washington, Mark P Burns
The apolipoprotein E (apoE) protein is involved in clearance of β-amyloid (Aβ) from the brain; and the APOE4 gene is associated with Aβ plaque formation in humans following traumatic brain injury (TBI). Here, we examined the association between apoE and Aβ40 after experimental TBI and the effects of APOE alleles on this relationship. We report a biphasic response of soluble apoE protein after TBI with an acute reduction at 1 day postinjury followed by an increase at 7 days postinjury. TBI-induced Aβ40 levels decreased as soluble apoE levels increased...
June 12, 2016: Journal of Neuropathology and Experimental Neurology
Songli Wang, Paul Wen, Stephen Wood
Alzheimer's disease (AD) is characterized pathologically by the presence of amyloid plaques and neurofibrillary tangles.  The amyloid hypothesis contends that the abnormal accumulation of Aβ, the principal component of amyloid plaques, plays an essential role in initiating the disease.  Impaired clearance of soluble Aβ from the brain, a process facilitated by apolipoprotein E (APOE), is believed to be a contributing factor in plaque formation.  APOE expression is transcriptionally regulated through the action of a family of nuclear receptors including the peroxisome proliferator-activated receptor gamma and liver X receptors (LXRs) in coordination with retinoid X receptors (RXRs)...
2016: F1000Research
Jianjun Zhong, Chongjie Cheng, Han Liu, Zhijian Huang, Yue Wu, Zhipeng Teng, Junchi He, Hongrong Zhang, Jinchuan Wu, Fang Cao, Li Jiang, Xiaochuan Sun
Bexarotene has been proved to have neuroprotective effects in many animal models of neurological diseases. However, its neuroprotection in traumatic brain injury (TBI) is still unknown. This study aims to explore the neuroprotective effects of bexarotene on TBI and its possible mechanism. Controlled cortical impact (CCI) model was used to simulate TBI in C57BL/6 mice as well as APOE gene knockout (APOE-KO) mice. After CCI, mice were daily dosed with bexarotene or vehicle solution intraperitoneally. The motor function, learning and memory, inflammatory factors, microglia amount, apoptosis condition around injury site and main side-effects were all measured...
May 25, 2016: Neuroscience
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