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https://www.readbyqxmd.com/read/29775538/discovery-of-potent-and-centrally-active-6-substituted-5-fluoro-1-3-dihydro-oxazine-%C3%AE-secretase-bace1-inhibitors-via-active-conformation-stabilization
#1
Kenji Nakahara, Kouki Fuchino, Kazuo Komano, Naoya Asada, Genta Tadano, Tsuyoshi Hasegawa, Takahiko Yamamoto, Yusuke Sako, Masayoshi Ogawa, Chie Unemura, Motoko Hosono, Hisanori Ito, Gaku Sakaguchi, Shigeru Ando, Shuichi Ohnishi, Yasuto Kido, Tamio Fukushima, Deborah Dhuyvetter, Herman Borghys, Harrie J M Gijsen, Yoshinori Yamano, Yasuyoshi Iso, Ken-Ichi Kusakabe
β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analog of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29774122/the-down-regulation-of-the-cyp2c19-gene-is-associated-with-aggressive-tumor-potential-and-the-poorer-recurrence-free-survival-of-hepatocellular-carcinoma
#2
Ryo Ashida, Yukiyasu Okamura, Keiichi Ohshima, Yuko Kakuda, Katsuhiko Uesaka, Teiichi Sugiura, Takaaki Ito, Yusuke Yamamoto, Takashi Sugino, Kenichi Urakami, Masatoshi Kusuhara, Ken Yamaguchi
Project HOPE (High-tech Omics-based Patient Evaluation) began in 2014 using integrated gene expression profiling (GEP) of cancer tissues as well as diathesis of each patient who underwent an operation at our institution. The aim of this study was to clarify the association between the expression of cytochrome P450s (CYP) genes and recurrence of hepatocellular carcinoma (HCC). The present study included 92 patients. Genes with aberrant expression were selected based on a ≥10-fold difference in the expression between tumor and non-tumor tissues...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29773554/nitidine-chloride-is-a-mechanism-based-inactivator-of-cyp2d6
#3
Xu Mao, Zi Xia Hu, Qian Wang, Na Zhang, Shen Zhi Zhou, Ying Peng, Jiang Zheng
Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (Roxb.) DC, a widely used traditional herbal medicine. NC has been reported to reveal multiple pharmacologic properties. The inhibitory effects of NC on human cytochrome P450 enzymes were investigated in the present study. We found that NC caused time- and concentration-dependent inhibition of CYP2D6, and more than 50% of CYP2D6 activity was suppressed after 15 min incubation with NC at 100 μM in the primary incubation mixtures, with KI of 4...
May 17, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29768302/pharmacogenomics-in-papua-new-guineans-unique-profiles-and-implications-for-enhancing-drug-efficacy-while-improving-drug-safety
#4
Joseph D Tucci, Paul P Pumuye, Nuala A Helsby, Daniel T Barratt, Percy P Pokeya, Francis Hombhanje, Andrew A Somogyi
Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide...
June 2018: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/29762875/in-vivo-assessment-of-the-effect-of-cyp1a2-inhibition-and-induction-on-pomalidomide-pharmacokinetics-in-healthy-subjects
#5
Yan Li, Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Matthew Hoffmann, Maria Palmisano, Simon Zhou
Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies...
May 15, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29749249/hplc-high-resolution-mass-spectrometry-with-polarity-switching-for-increasing-throughput-of-human-in-vitro-cocktail-drug-drug-interaction-assay
#6
Ragu Ramanathan, Anima Ghosal, Lakshmi Ramanathan, Kate Comstock, Helen Shen, Dil Ramanathan
AIM: Evaluation of HPLC-high-resolution mass spectrometry (HPLC-HRMS) full scan with polarity switching for increasing throughput of human in vitro cocktail drug-drug interaction assay. MATERIALS & METHODS: Microsomal incubates were analyzed using a high resolution and high mass accuracy Q-Exactive mass spectrometer to collect integrated qualitative and quantitative (Qual/Quant) data. RESULTS: Within assay, positive-to-negative polarity switching HPLC-HRMS method allowed quantification of eight and two probe compounds in the positive and negative ionization modes, respectively, while monitoring for LOR and its metabolites...
May 11, 2018: Bioanalysis
https://www.readbyqxmd.com/read/29746361/prolonged-qrs-widening-after-aripiprazole-overdose
#7
Maryann Mazer-Amirshahi, Robert Porter, Kayla Dewey
BACKGROUND: Aripiprazole is an atypical antipsychotic with a long half-life. Overdose can result in protracted somnolence and cardiac disturbances, particularly QT interval prolongation. METHODS: This is a single case report of a 14-year-old boy who took an overdose of aripiprazole and developed QRS widening. CASE: A 14-year-old boy intentionally ingested 20 tablets of aripiprazole (5 mg). He was brought to the emergency department when his ingestion was discovered...
May 5, 2018: Pediatric Emergency Care
https://www.readbyqxmd.com/read/29744741/effect-of-naltrexone-hydrochloride-on-cytochrome-p450-1a2-2c9-2d6-and-3a4-activity-in-human-liver-microsomes
#8
Haitham AlRabiah, Abdul Ahad, Gamal A E Mostafa, Fahad I Al-Jenoobi
BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated. METHODS: A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride...
May 9, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29742281/analyzing-the-clinical-actionability-of-germline-pharmacogenomic-findings-in-oncology
#9
Rebecca Wellmann, Brittany A Borden, Keith Danahey, Rita Nanda, Blase N Polite, Walter M Stadler, Mark J Ratain, Peter H O'Donnell
BACKGROUND: Germline and tumor pharmacogenomics impact drug responses, but germline markers less commonly guide oncology prescribing. The authors hypothesized that a critical number of clinically actionable germline pharmacogenomic associations exist, representing clinical implementation opportunities. METHODS: In total, 125 oncology drugs were analyzed for positive germline pharmacogenomic associations in journals with impact factors ≥5. Studies were assessed for design and genotyping quality, clinically relevant outcomes, statistical rigor, and evidence of drug-gene effects...
May 9, 2018: Cancer
https://www.readbyqxmd.com/read/29742109/effect-of-single-dose-imipramine-on-chronic-low-back-and-experimental-pain-a-randomized-controlled-trial
#10
Jürg Schliessbach, Andreas Siegenthaler, Lukas Bütikofer, Andreas Limacher, Peter Juni, Pascal H Vuilleumier, Ulrike Stamer, Lars Arendt-Nielsen, Michele Curatolo
Antidepressants are frequently prescribed as co-analgesics in chronic pain. While their efficacy is well documented for neuropathic pain, the evidence is less clear in musculoskeletal pain conditions. The present study therefore evaluated the effect of the tricyclic antidepressant imipramine on chronic low-back pain in a randomized, double-blinded placebo-controlled design. To explore the mechanisms of action and the influence of drug metabolism, multimodal quantitative sensory tests (QST) and genotyping for cytochrome P450 2D6 (CYP2D6) were additionally performed...
2018: PloS One
https://www.readbyqxmd.com/read/29738669/cypreact-a-software-tool-for-in-silico-reactant-prediction-for-human-cytochrome-p450-enzymes
#11
Siyang Tian, Yannick Djoumbou, Russ Greiner, David S Wishart
In silico metabolism prediction requires first predicting whether a specific molecule will interact with one or more specific metabolizing enzymes, then predicting the result of each enzymatic reaction. Here, we provide a computational tool, CypReact, for performing this first task of reactant prediction. Specically, CypReact takes as input an arbitrary molecule (specied as a SMILES string or a standard SDF file), and any one of the nine of the most important human cytochrome P450 (CYP450) enzymes -- CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 -- and accurately predicts whether the query molecule will react with that given CYP450 enzyme...
May 8, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29737183/clozapine-toxicity-in-a-cyp2d6-poor-metaboliser-additive-effects-of-haloperidol-and-valproate-on-clozapine-metabolism
#12
Robert Reznik, Rena Yuan Yuan Chen, Phoebe Stanford
OBJECTIVE: To illustrate the complexities of clozapine metabolism with the use of therapeutic drug monitoring. METHODS: We describe a case of clozapine toxicity in a patient with schizophrenia treated with the combination of clozapine, valproate and haloperidol. RESULTS: A 24-year-old CYP2D6 poor metaboliser developed clozapine toxicity corresponding to the additive effects of haloperidol, and increasing clozapine and valproate doses. Saturation of metabolism, evidenced by a high clozapine/norclozapine ratio, was present at this time...
May 1, 2018: Australasian Psychiatry: Bulletin of Royal Australian and New Zealand College of Psychiatrists
https://www.readbyqxmd.com/read/29735754/an-assessment-of-the-in-vitro-inhibition-of-cytochrome-p450-enzymes-cyp-udp-glucuronsyltransferases-ugt-and-transporters-by-phosphodiester-or-phosphorothioate-linked-oligonucleotides
#13
Faraz Kazmi, Phyllis Yerino, Chase McCoy, Andrew Parkinson, David B Buckley, Brian W Ogilvie
Oligonucleotides represent an expanding class of pharmacotherapeutics in development for various indications. Typically, oligonucleotides are developed with phosphorothioate linkages for the improvement of biological stability; however limited data are available on the potential of these molecules to cause drug-drug interactions (DDIs). In the present study, two non therapeutic oligonucleotides with either phosphodiester (PD-GP and PD-Ac) or phosphorothioate (PT-GP and PT-Ac) linkages were evaluated in vitro for their potential to inhibit P450s and UGTs in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHH) and to inhibit select transporters in expression systems...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29734517/rosuvastatin-induced-rhabdomyolysis-possible-role-of-ticagrelor-and-patients-pharmacogenetic-profile
#14
Majda Vrkić Kirhmajer, Viola Macolić Šarinić, Livija Šimičević, Iva Ladić, Krešimir Putarek, Ljiljana Banfić, Nada Božina
Up to the beginning of 2018, a total of eight cases describing rare but clinically important drug interactions between rosuvastatin and ticagrelor which resulted in rhabdomyolysis have been noted in the Global World Health Organization (WHO) adverse drug reaction (ADR) database (VigiBase) as well as in available literature. There are several possible factors which could contribute to the onset of rhabdomyolysis: old age, initially excessive rosuvastatin dose, drug-drug interactions (DDI) on metabolic enzymes (CYPs and UGTs) and drug transporter levels (ABCB1, ABCG2, OATP1B1) and pharmacogenetic predisposition...
May 7, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29728928/effects-of-diltiazem-a-moderate-inhibitor-of-cyp3a4-on-the-pharmacokinetics-of-tamsulosin-in-different-cyp2d6-genotypes
#15
Ji-Yeong Byeon, Yun Jeong Lee, Young-Hoon Kim, Se-Hyung Kim, Choong-Min Lee, Jung-Woo Bae, Choon-Gon Jang, Seok-Yong Lee, Chang-Ik Choi
Tamsulosin, a selective antagonist of the α1 -adrenoceptor, is primarily metabolized by CYP3A4 and CYP2D6, and tamsulosin exposure is significantly increased according to the genetic polymorphism of CYP2D6. In this study, we investigated the effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in subjects with different CYP2D6 genotypes. Twenty-three healthy Korean male subjects with CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, two-phase parallel pharmacokinetic study...
May 4, 2018: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29725907/genetic-factors-associated-with-postoperative-nausea-and-vomiting-a-systematic-review
#16
Pedro López-Morales, Diego Flores-Funes, Elena González Sánchez-Migallón, Ramón José Lirón-Ruiz, José Luis Aguayo-Albasini
BACKGROUND: In previous studies, there seems to be a relationship between different genetic polymorphisms and postoperative nausea and vomiting (PONV). We perform a systematic review of the current literature about the relationship between genetic polymorphisms and the presence of PONV. METHODS: Two bibliographic searches were carried out in three databases (PubMed, Web of Science, and Scopus) of studies, preferably prospective, about PONV following abdominal surgery...
May 3, 2018: Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract
https://www.readbyqxmd.com/read/29724589/discovery-of-evocalcet-a-next-generation-calcium-sensing-receptor-agonist-for-the-treatment-of-hyperparathyroidism
#17
Hiroshi Miyazaki, Yousuke Ikeda, Osamu Sakurai, Tsutomu Miyake, Rie Tsubota, Jyunko Okabe, Masataka Kuroda, Yutaka Hisada, Tetsuya Yanagida, Hikaru Yoneda, Yukihito Tsukumo, Shin Tokunaga, Takehisa Kawata, Rikiya Ohashi, Hajime Fukuda, Koki Kojima, Ayako Kannami, Takayuki Kifuji, Naoya Sato, Akiko Idei, Taku Iguchi, Tetsuya Sakairi, Yasunori Moritani
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist...
April 24, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29719052/effect-of-single-walled-carbon-nanotubes-on-cytochrome-p450-activity-in-human-liver-microsomes-in-vitro
#18
Yuki Asai, Yukiko Sakakibara, Rina Inoue, Rikako Inoue, Masayuki Nadai, Miki Katoh
Single-walled carbon nanotubes (SWCNTs) are made from a rolled single sheet of graphene with a diameter in the nanometer range. SWCNTs are potential carriers for drug delivery systems because antibodies or drugs can be loaded on their surface; however, their effect on the activities of cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the effect of two kinds of SWCNTs with different lengths (FH-P- and SO-SWCNTs) on human CYP activity. In addition, other nano-sized carbon materials, such as carbon black, fullerene-C60 , and fullerene-C70 were also evaluated to compare their effects on CYP activities...
May 2, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29714124/clinical-application-of-pharmacogenetics-in-pain-management
#19
D Max Smith, Kristin W Weitzel, Larisa H Cavallari, Amanda R Elsey, Siegfried Of Schmidt
There is growing experience translating genomic data into clinical practice, as seen with the Implementing GeNomics In pracTicE (IGNITE) network. A primary example is the influence of CYP2D6 genotype on the beneficial and adverse effects of some opioids. Clinical recommendations exist to guide drug therapy based on CYP2D6 genotype for codeine, tramadol, oxycodone and hydrocodone, although the level of supporting evidence differs by drug. Limited evidence also supports the use of genetic data to guide other medications in chronic pain therapy, including tricyclic antidepressants and celecoxib...
March 2018: Personalized Medicine
https://www.readbyqxmd.com/read/29702137/reduced-clearance-of-venlafaxine-in-a-combined-treatment-with-quetiapine
#20
Michael Paulzen, Georgios Schoretsanitis, Christoph Hiemke, Gerhard Gründer, Ekkehard Haen, Marc Augustin
Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic interactions between venlafaxine and quetiapine have not been studied yet. A therapeutic drug monitoring database containing serum concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. Two groups of patients were compared: venlafaxine monotherapy V0 (n = 153) and co-medication with quetiapine, VQUE (n = 71)...
April 24, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
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