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https://www.readbyqxmd.com/read/29202402/design-synthesis-and-biological-evaluation-of-a-series-of-resorcinol-based-n-benzyl-benzamide-derivatives-as-potent-hsp90-inhibitors
#1
Sun You Park, Yong Jin Oh, Yunmee Lho, Ju Hui Jeong, Kwang-Hyeon Liu, Jaeyoung Song, Soong-Hyun Kim, Eunyoung Ha, Young Ho Seo
Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975...
November 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29189941/vortioxetine-clinical-pharmacokinetics-and-drug-interactions
#2
REVIEW
Grace Chen, Astrid-Maria Højer, Johan Areberg, George Nomikos
Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed...
November 30, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29183231/in-silico-prediction-of-multiple-category-classification-model-for-cytochrome-p450-inhibitors-and-non-inhibitors-using-machine-learning-method
#3
J H Lee, S Basith, M Cui, B Kim, S Choi
The cytochrome P450 (CYP) enzyme superfamily is involved in phase I metabolism which chemically modifies a variety of substrates via oxidative reactions to make them more water-soluble and easier to eliminate. Inhibition of these enzymes leads to undesirable effects, including toxic drug accumulations and adverse drug-drug interactions. Hence, it is necessary to develop in silico models that can predict the inhibition potential of compounds for different CYP isoforms. This study focused on five major CYP isoforms, including CYP1A2, 2C9, 2C19, 2D6 and 3A4, that are responsible for more than 90% of the metabolism of clinical drugs...
October 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/29178685/clinical-and-genetic-predictors-of-delayed-remission-after-multiple-levels-of-antidepressant-treatment-toward-early-identification-of-depressed-individuals-for-advanced-care-options
#4
Michael I Falola, Nita Limdi, Richard C Shelton
OBJECTIVE: To identify clinical and genetic characteristics that can be used to recognize depressed patients who are likely to respond quickly versus those who will have a more delayed response following multiple treatment trials. METHODS: The data used were obtained from the National Institute of Mental Health-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was conducted between July 2001 and September 2006. Of the 4,041 treatment-naive participants in the original study, 1,953 with DNA samples were included...
November 21, 2017: Journal of Clinical Psychiatry
https://www.readbyqxmd.com/read/29176019/in-vitro-modulation-of-the-cytochrome-p450-and-abcb1-p-glycoprotein-activities-of-the-aqueous-extract-of-allophylus-cominia-l-sw-leaves
#5
Carlos L Pérez, Maria T Donato, Ivones Hernández, Miriam T Paz Lopes, Evangelina Marrero, Jose A Herrera, Maria J Gómez-Lechón, Idania Rodeiro
BACKGROUND: The aqueous extract of the Allophylus cominia (L) Sw (Sapindaceae) leaves has shown anti-diabetic, anti-obesity and anti-inflammatory properties. In the Caribbean region, it is typically used for the treatment of type-2 diabetes. METHODS: Considering the herb-drug interaction, the aim of this study was to evaluate the potential effects of the A. cominia extract on the cytochrome P450 (CYP) (rat hepatocyte model) and P-glycoprotein (P-gp) (4T1 cell line) systems...
November 25, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29133569/efficacy-of-tilorone-dihydrochloride-against-ebola-virus-infection
#6
Sean Ekins, Mary A Lingerfelt, Jason E Comer, Alexander N Freiberg, Jon C Mirsalis, Kathleen O'Loughlin, Anush Harutyunyan, Claire McFarlane, Carol E Green, Peter B Madrid
Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside of the US. A machine learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9 and 1A2)...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29120380/in-vitro-phase-i-metabolism-of-crv431-a-novel-oral-drug-candidate-for-chronic-hepatitis-b
#7
Daniel J Trepanier, Daren R Ure, Robert T Foster
The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0-80 min with CRV431, and the metabolite profile was assessed by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS). CRV431 was extensively metabolized through oxidation to produce various hydroxylated and demethylated species...
November 9, 2017: Pharmaceutics
https://www.readbyqxmd.com/read/29117660/nebivolol-induced-hyperkalemia-case-report
#8
Karmela Altabas, Velimir Altabas, Tonko Gulin
In this article, we document a conclusive case of nebivolol-induced hyperkalemia for the first time in the known medical literature. Hyperkalemia is associated with serious conditions such as cardiac arrhythmias and sudden cardiac death. Nebivolol was not known to cause hyperkalemia, and this event is not listed in its summary of product characteristics (SmPC). For older beta blockers, hyperkalemia is recognized as a rare adverse event linked to cytochrome P450 2D6 (CYP2D6) polymorphism and poor drug degradation...
December 2016: Acta Clinica Croatica
https://www.readbyqxmd.com/read/29096568/preclinical-evaluation-of-safety-of-fucoidan-extracts-from-undaria-pinnatifida-and-fucus-vesiculosus-for-use-in-cancer-treatment
#9
Lata Mathew, Maryam Burney, Anjali Gaikwad, Pranavand Nyshadham, Elizabeth K Nugent, Anneliese Gonzalez, Judith A Smith
OBJECTIVES: To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo studies were done to confirm safety and investigate fucoidan-mediated immune modulation. METHODS: Cytochrome P450 (CYP450) 3A4, 2C8, 2C9, and 2D6 inhibition experiments were conducted in vitro followed by an ex vivo human hepatocytes model to evaluate the CYP450 induction potential of each fucoidan at highest theoretical concentrations...
December 2017: Integrative Cancer Therapies
https://www.readbyqxmd.com/read/29054967/prediction-of-cytochrome-p450-mediated-drug-clearance-in-humans-based-on-the-measured-activities-of-selected-cyps
#10
Jie Gao, Jie Wang, Na Gao, Xin Tian, Jun Zhou, Yan Fang, Hai-Feng Zhang, Qiang Wen, Lin-Jing Jia, Dan Zou, Hai-Ling Qiao
Determining drug-metabolizing enzyme activities on an individual basis is an important component of personalized medicine, and cytochrome P450 enzymes (CYPs) play a principal role in hepatic drug metabolism. Herein, a simple method for predicting the major CYP-mediated drug clearance in vitro and in vivo is presented. Ten CYP-mediated drug metabolic activities in human liver microsomes (HLMs) from 105 normal liver samples were determined. The descriptive models for predicting the activities of these CYPs in HLMs were developed solely on the basis of the measured activities of a smaller number of more readily assayed CYPs...
October 20, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29044450/antipsychotic-therapy-amongst-cytochrome-p450-2d6-poor-metabolizers-in-the-clinical-practice-a-case-report
#11
Laura Espinosa-Martínez, Adriana Fortea, Giovanni Oriolo, Alexandre González-Rodríguez, Mercè Brunet, Virginia Fortuna, Eduard Parellada
No abstract text is available yet for this article.
September 2017: Actas Españolas de Psiquiatría
https://www.readbyqxmd.com/read/28994497/effects-of-vernonia-cinerea-compounds-on-drug-metabolizing-cytochrome-p450s-in-human-liver-microsomes
#12
Phisit Pouyfung, Songklod Sarapusit, Pornpimol Rongnoparut
Vernonia cinerea has been widely used in traditional medicines for various diseases and shown to aid in smoking abstinence and has anticancer properties. V. cinerea bioactive compounds, including flavonoids and hirsutinolide-type sesquiterpene lactones, have shown an inhibition effect on the nicotine-metabolizing cytochrome P450 2A6 (CYP2A6) enzyme and hirsutinolides reported suppressing cancer growth. In this study, V. cinerea ethanol extract and its bioactive compounds, including four flavonoids and four hirsutinolides, were investigated for an inhibitory effect on human liver microsomal CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 using cocktail inhibition assays combined with LC-MS/MS analysis...
October 10, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28990182/effect-of-chronic-kidney-disease-on-nonrenal-elimination-pathways-a-systematic-assessment-of-cyp1a2-cyp2c8-cyp2c9-cyp2c19-and-oatp
#13
Ming-Liang Tan, Kenta Yoshida, Ping Zhao, Lei Zhang, Thomas D Nolin, Micheline Piquette-Miller, Aleksandra Galetin, Shiew-Mei Huang
Our recent studies have shown that chronic kidney disease (CKD) affects the pharmacokinetics (PKs) of cytochrome P450 (CYP)2D6-metabolized drugs, whereas effects were less evident on CYP3A4/5. Therefore, the effect of CKD on the disposition of CYP1A2-metabolized, CYP2C8-metabolized, CYP2C9-metabolized, CYP2C19-metabolized, and organic anion-transporting polypeptide (OATP)-transported drugs was investigated. We identified dedicated CKD studies with 6, 5, 6, 4, and 12 "model" substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP, respectively...
October 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28955222/improved-prediction-of-endoxifen-metabolism-by-cyp2d6-genotype-in-breast-cancer-patients-treated-with-tamoxifen
#14
Werner Schroth, Stefan Winter, Thomas Mürdter, Elke Schaeffeler, Diana Eccles, Bryony Eccles, Balram Chowbay, Chiea C Khor, Arafat Tfayli, Nathalie K Zgheib, Michel Eichelbaum, Matthias Schwab, Hiltrud Brauch
Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual's capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings. Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28934153/inhibitory-effect-of-selaginellins-from-selaginella-tamariscina-beauv-spring-against-cytochrome-p450-and-uridine-5-diphosphoglucuronosyltransferase-isoforms-on-human-liver-microsomes
#15
Jae-Kyung Heo, Phi-Hung Nguyen, Won Cheol Kim, Nguyen Minh Phuc, Kwang-Hyeon Liu
Selaginella tamariscina (Beauv.) has been used for traditional herbal medicine for treatment of cancer, hepatitis, and diabetes in the Orient. Numerous bioactive compounds including alkaloids, flavonoids, lignans, and selaginellins have been identified in this medicinal plant. Among them, selaginellins having a quinone methide unit and an alkylphenol moiety have been known to possess anticancer, antidiabetic, and neuroprotective activity. Although there have been studies on the biological activities of selaginellins, their modulatory potential of cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyltransferase (UGT) activities have not been previously evaluated...
September 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28920579/point-of-care-companion-diagnostic-tests-for-personalizing-psychiatric-medications-fulfilling-an-unmet-clinical-need
#16
Anil S Modak
Over the last decade stable isotope labeled substrates have been used as probes for rapid, point of care, non invasive and user friendly phenotype breath tests to evaluate activity of drug metabolizing enzymes. These diagnostic breath tests can be potentially used as Companion diagnostics (CDx) by physicians to personalize medications especially psychiatric drugs with narrow therapeutic windows, to monitor the progress of disease severity, medication efficacy and to study in vivo the pharmacokinetics of xenobiotics, Several genotype tests have been approved by the FDA over the last 15 years, however, they have not been cleared for use in personalizing medications since they fall woefully short in identifying all non responders to drugs especially for the CYP450 enzymes...
September 18, 2017: Journal of Breath Research
https://www.readbyqxmd.com/read/28917081/evaluation-of-the-ecstasy-influence-on-tramadol-and-its-main-metabolite-plasma-concentration-in-rats
#17
Bardia Jamali, Behjat Sheikholeslami, Yalda Hosseinzadeh Ardakani, Hoda Lavasani, Mohammad-Reza Rouini
BACKGROUND: Tramadol is prone to be abused alone, or in combination with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication...
September 26, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28916283/deuterated-d6-dextromethorphan-elicits-antidepressant-like-effects-in-mice
#18
Linda Nguyen, Anna L Scandinaro, Rae R Matsumoto
The over-the-counter antitussive dextromethorphan (DM) may have rapid antidepressant actions based on its overlapping pharmacology with ketamine, which has shown fast antidepressant effects but whose widespread use remains limited by problematic side effects. We have previously shown that DM produces antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST) that are mediated in part through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic (AMPA) and sigma-1 receptors, two protein targets associated with a faster onset of antidepressant efficacy...
October 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28871472/cytochrome-p450-2d6-and-parkinson-s-disease-polymorphism-metabolic-role-risk-and-protection
#19
REVIEW
Mohd Sami Ur Rasheed, Abhishek Kumar Mishra, Mahendra Pratap Singh
Cytochrome P450 (CYP) 2D6 is one of the most highly active, oxidative and polymorphic enzymes known to metabolize Parkinsonian toxins and clinically established anti-Parkinson's disease (PD) drugs. Albeit CYP2D6 gene is not present in rodents, its orthologs perform almost the similar function with imprecise substrate and inhibitor specificity. CYP2D6 expression and catalytic activity are found to be regulated at every stage of the central dogma except replication as well as at the epigenetic level. CYP2D6 gene codes for a set of alternate splice variants that give rise to a range of enzymes possessing variable catalytic activity...
December 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28866862/acetylshikonin-is-a-novel-non-selective-cytochrome-p450-inhibitor
#20
Jong Cheol Shon, Nguyen Minh Phuc, Won Cheol Kim, Jae Kyung Heo, Zhexue Wu, Hyunyoung Lee, Kwang-Hyeon Liu
Acetylshikonin is biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the root of Lithospermum erythrorhizoma. We have recently discovered a inhibitory effect of acetylshikonin against CYP2J2 activity. Based on this result, we expanded our study to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed strong inhibitory effect against all P450s tested with IC50 values of 1...
September 3, 2017: Biopharmaceutics & Drug Disposition
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