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https://www.readbyqxmd.com/read/29228376/effects-of-cyclophosphamide-cyp-and-or-doxorubicin-dox-in-a-murine-model-of-post-chemotherapy-cognitive-impairment
#1
Timothy J Flanigan, Julie E Anderson, Ikram Elayan, Antiño R Allen, Sherry A Ferguson
Post-chemotherapy cognitive impairment, or PCCI, is a common complaint, particularly among breast cancer patients. However, the exact nature of PCCI appears complex. To model the human condition, ovariectomized C57BL/6J mice were treated iv weekly for 4 weeks with saline, 2 mg/kg doxorubicin (DOX), 50 mg/kg cyclophosphamide (CYP), or DOX+CYP. For the subsequent 10 weeks, mice were assessed on several behavioral tests, including those measuring spatial learning and memory. After sacrifice, hippocampal spine density and morphology in the dentate gyrus, CA1, and CA3 regions were measured...
December 7, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29226313/model-based-assessments-of-cyp-mediated-drug-drug-interaction-risk-of-alectinib-physiologically-based-pharmacokinetic-modeling-supported-clinical-development
#2
Yumi Cleary, Michael Gertz, Peter N Morcos, Li Yu, Kuresh Youdim, Alex Phipps, Stephen Fowler, Neil Parrott
Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfil the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was taken to ensure extrapolation ability of DDI risk...
December 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29226135/a-novel-cyclophilin-b-gene-in-the-red-tide-dinoflagellate-cochlodinium-polykrikoides-molecular-characterizations-and-transcriptional-responses-to-environmental-stresses
#3
Sofia Abassi, Hui Wang, Bum Soo Park, Jong-Woo Park, Jang-Seu Ki
The marine dinoflagellate Cochlodinium polykrikoides is one of the most common ichthyotoxic species that causes harmful algal blooms (HABs), which leads to ecological damage and huge economic loss in aquaculture industries. Cyclophilins (CYPs) belong to the immunophilin superfamily, and they may play a role in the survival mechanisms of the dinoflagellate in stress environments. In the present study, we identified a novel cyclophilin gene from C. polykrikoides and examined physiological and gene transcriptional responses to biocides copper sulphate (CuSO4) and sodium hypochlorite (NaOCl)...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29224415/preclinical-evaluation-of-saroglitazar-magnesium-a-dual-ppar-%C3%AE-%C3%AE-agonist-for-treatment-of-dyslipidemia-and-metabolic-disorders
#4
Harilal Patel, Poonam Giri, Prakash Patel, Sanjay Singh, Laxmikant Gupta, Urvesh Patel, Nirav Modi, Kalpesh Shah, Mukul R Jain, Nuggehally R Srinivas, Pankaj Patel
Saroglitazar, a novel peroxisome proliferator-activated receptor agonist (PPAR), regulates lipid and glucose metabolism. The objective of this report is to provide a preclinical evaluation (in vitro/in vivo) of ADME properties of saroglitazar. In vitro studies included determination of permeability, metabolic stability, plasma protein binding, CYP reaction phenotyping and CYP inhibitory liability. In vivo studies included oral bioavailability and pharmacokinetic assessment in mouse, rat and dog. The excretion of saroglitazar was determined in rats...
December 9, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29223619/differential-effects-of-hepatic-cirrhosis-on-the-intrinsic-clearances-of-sorafenib-and-imatinib-by-cyps-in-human-liver
#5
Michael Murray, Tina B Gillani, Sussan Ghassabian, Robert J Edwards, Tristan Rawling
The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity...
December 6, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29217084/oral-phenytoin-protects-against-experimental-cyclophosphamide-chemotherapy-induced-hair-loss
#6
A Y Onaolapo, A A Adebayo, O J Onaolapo
In the current study, effects of oral phenytoin on hair growth in cyclophosphamide-treated rats were assessed with the goal of evaluating the ability of phenytoin to suppress chemotherapy-induced hair loss. Thirty-six rats were randomly assigned to six groups (1k6) of six each (n=6). In all groups, anagen was induced in flank skin of rats by depilation. On day 9 (anagen VI), rats were injected once with either distilled water (groups 1-3) or cyclophoshamide (groups 4-6). From day 10, rats in group 1 and 4 received oral vehicle (distilled water), groups 2 and 5 received oral phenytoin (50mg/kg), while groups 3 and 6 also received oral phenytoin (100mg/kg)...
December 4, 2017: Pathophysiology: the Official Journal of the International Society for Pathophysiology
https://www.readbyqxmd.com/read/29215266/use-of-phenoxyaniline-analogs-to-generate-biochemical-insights-into-polybrominated-diphenyl-ether-interaction-with-cyp2b-enzymes
#7
Chao Chen, Jingbao Liu, James R Halpert, P Ross Wilderman
Human hepatic cytochromes P450 (CYP) are integral to xenobiotic metabolism. CYP2B6 is a major catalyst of biotransformation of environmental toxicants including polybrominated diphenyl ethers (PBDEs). CYP2B substrates tend to contain halogen atoms, but the biochemical basis for this selectivity and for species specific determinants of metabolism has not been identified. Spectral binding titrations and inhibition studies were performed to investigate interactions of rat CYP2B1, rabbit CYP2B4, and CYP2B6 with a series of phenoxyaniline (POA) congeners that are analogs of PBDEs...
December 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/29215040/sex-related-pharmacokinetic-differences-and-mechanisms-of-metapristone-ru486-metabolite
#8
Wenge Chen, Yingying Xiao, Jianzhong Chen, Jian Liu, Jingwei Shao, Tao Li, Yewei Zhu, Ji Ma, Yu Gao, Jichuang Wang, Jianguo Xu, Yusheng Lu, Lee Jia
Metapristone is the primary metabolite of the abortifacient mifepristone (RU486), and is being developed as a safe and effective cancer metastatic chemopreventive agent for both sexes. Here, we systematically investigated the sex-related pharmacokinetics of metapristone in both rats and dogs, and explored the related mechanisms of actions. Administration of metapristone to rats and dogs showed that plasma concentrations of metapristone (AUC, C max ) were significantly higher in female dogs and rats than in males...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29205871/pharmacogenetic-analysis-of-the-model-based-pharmacokinetics-of-five-anti-hiv-drugs-how-does-this-influence-the-effect-of-aging
#9
Jingxian Chen, Farida S Akhtari, Michael J Wagner, Oscar Suzuki, Tim Wiltshire, Alison A Motsinger-Reif, Julie B Dumond
Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV-infected patients. Seventy-four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging-PGx-PK association and interaction analyses were conducted using one-way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P-glycoprotein (P-gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants...
December 3, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/29202738/effects-of-mistletoe-products-on-pharmacokinetic-drug-turnover-by-inhibition-and-induction-of-cytochrome-p450-activities
#10
Michael Schink, Oliver Dehus
BACKGROUND: European mistletoe (Viscum album) products used in cancer therapy are frequently combined with other anti-cancer-drugs. Hence, potential herb-drug interactions have become a major safety concern in mistletoe therapy. METHODS: Three European mistletoe products (Helixor® A, Helixor® M and Helixor® P from mistletoe grown on firs, apple trees and pines, respectively) were tested for inhibition of nine major cytochrome P450 (CYP) isoenzymes in a test system using pooled human liver microsomes and for induction of five CYP isoforms in human hepatocytes cultivated in vitro according to the relevant guideline...
December 4, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/29202140/relation-of-the-polymorphism-of-cyp51a-sequence-and-the-susceptibility-of-aspergillus-fumigatus-isolates-to-triazoles-determined-by-commercial-gradient-test-etest-and-by-reference-methods
#11
Urszula Nawrot, Beata Sulik-Tyszka, Ewelina Kurzyk, Martyna Mroczyńska, Katarzyna Włodarczyk, Marta Wróblewska, Grzegorz Władysław Basak, Anna Brillowska-Dąbrowska
The aim of this study was to evaluate the accuracy of commercial gradient test (Etest) in the detection of triazole resistant Aspergillus fumigatus isolates using reference microdilution methods and the analysis of sequences of the cyp 51A gene. The study was performed on twenty clinical isolates which were identified as Aspergillus fumigatus based on the DNA sequences of the ITS1-2 fragment of ribosomal DNA and the β-tubulin gene, out of them seventeen isolates showed wild -type cyp51A sequence and three were positive for the mutation TR34/L98H...
November 30, 2017: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/29198170/the-effects-of-aging-on-hepatic-microsomal-scaling-factor-and-hepatocellularity-number-in-the-horse
#12
Khaled A Shibany, Sabine Tötemeyer, Stefanie L Pratt, Stuart W Paine
Scaling factor values for the in vitro-in vivo extrapolation of hepatic metabolic clearance for xenobiotics have not yet been determined in horses. Scaling factors were determined by comparing the total protein and or CYP P450 content in microsomes and cryopreserved hepatocytes against the content in the liver. Microsomal protein per gram of liver (MPPGL) and hepatocellularity number per gram of liver (HPGL) using CYP P450 content method ranged 41 - 73 mg/gram of liver (mean= 57 mg/gram of liver, n = 39) and 146 - 320 × 106 cells/g of liver (mean = 227× 106 cells/g of liver, n = 18), respectively; and 156 - 352 × 106 cells/g of liver (mean = 232× 106 cells/g of liver) using total protein method...
December 2, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29196978/the-role-of-soluble-epoxide-hydrolase-enzyme-on-daunorubicin-mediated-cardiotoxicity
#13
Zaid H Maayah, Ghada Abdelhamid, Osama H Elshenawy, Ahmed A El-Sherbeni, Hassan N Althurwi, Erica McGinn, Doaa Dawood, Ahmad H Alammari, Ayman O S El-Kadi
Several studies have demonstrated the role of cytochrome P450 (CYP) and its associated arachidonic acid (AA) metabolites in the anthracyclines-induced cardiac toxicity. However, the ability of daunorubicin (DNR) to induce cardiotoxicity through the modulation of CYP and its associated AA metabolites has not been investigated yet. Therefore, we hypothesized that DNR-induced cardiotoxicity is mediated through the induction of cardiotoxic hydroxyeicosatetraenoic acids and/or the inhibition of cardioprotctive epoxyeicosatrienoic acids (EETs)...
December 1, 2017: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/29193126/pharmacokinetics-and-pharmacodynamics-of-azeloprazole-sodium-a-novel-proton-pump-inhibitor-in-healthy-japanese-volunteers
#14
Ryoko Toda, Masanari Shiramoto, Emi Komai, Kazuyoshi Yoshii, Masamichi Hirayama, Yoshihiro Kawabata
The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z-215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD of azeloprazole sodium have not been evaluated in Japanese subjects. We conducted an open-label, crossover study in healthy Japanese male volunteers to evaluate the plasma concentration and intragastric pH with respect to CYP2C19 genotype after repeated administration of 10, 20, and 40 mg azeloprazole sodium and 10 and 20 mg rabeprazole sodium (rabeprazole)...
November 28, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29192290/direct-conversion-of-human-fibroblasts-into-hepatocyte-like-cells-by-atf5-prox1-foxa2-foxa3-and-hnf4a-transduction
#15
Daiki Nakamori, Hiroki Akamine, Kazuo Takayama, Fuminori Sakurai, Hiroyuki Mizuguchi
Recently, it has been reported that human hepatocyte-like cells can be generated from fibroblasts by direct reprogramming technology. However, the conversion efficiency of human induced hepatocyte-like cells (hiHeps) is not high enough. In addition, comparative analysis with the existing models of hepatocytes, such as human iPS cell-derived hepatocyte-like cells and primary human hepatocytes, has not been sufficiently carried out. In this study, we screened hepatic transcription factors for efficient direct hepatic reprogramming and compared hepatic functions between hiHeps and other existing hepatocyte models...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29189189/selective-suppression-of-cyp3a4-mrna-and-enzyme-activity-by-epidermal-growth-factor-in-plated-human-hepatocytes
#16
George Zhang, Duan Wang, Thuy Ho, Robert J Clark, David M Stresser
BACKGROUND: Epidermal growth factor (EGF) is a well-known mitogen that has importance in cell proliferation and differentiation. These properties have led to the common use of EGF as an additive to some cell culture media. EGF has been previously shown to modulate constitutive cytochrome P450 (CYP) expression in vitro. OBJECTIVES: To assess the influence of EGF on the basal and induced expression of CYP3A4, CYP1A2 and CYP2B6 in plated human hepatocytes. METHODS: Human hepatocytes from 3 donors were treated with EGF with and without in the presence of positive control inducers...
November 28, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29188497/bexarotene-a-selective-rxr%C3%AE-agonist-reverses-hypotension-associated-with-inflammation-and-tissue-injury-in-a-rat-model-of-septic-shock
#17
Bahar Tunctan, Sefika P Kucukkavruk, Meryem Temiz-Resitoglu, Demet S Guden, Ayse N Sari, Seyhan Sahan-Firat
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that can activate or inhibit the expression of many target genes by forming a heterodimer complex with the retinoid X receptor (RXR). The aim of this study was to investigate effects of bexarotene, a selective RXRα agonist, on the changes in renal, cardiac, hepatic, and pulmonary expression/activity of inducible nitric oxide synthase (iNOS) and cytochrome P450 (CYP) 4F6 in relation to PPARα/β/γ-RXRα heterodimer formation in a rat model of septic shock...
November 29, 2017: Inflammation
https://www.readbyqxmd.com/read/29188056/molecular-cloning-expression-purification-and-functional-characterization-of-an-antifungal-cyclophilin-protein-from-panax-ginseng
#18
Hui Zhang, Jiawen Wang, Shuaijun Li, Siming Wang, Meichen Liu, Weinan Wang, Yu Zhao
Cyclophilins (CyPs), a member of peptidyl-prolyl cis-trans isomerases (PPIases), are ubiquitously distributed in organisms such as bacteria, yeast, plants and animals. CyPs have diverse biological functions, with some exhibiting antifungal and antiviral activities. In this study, Panax ginseng cyclophilin (pgCyP), a novel gene encoding an antifungal protein from Panax ginseng, was cloned, and its protein product was expressed in Escherichia coli, and then fractionated by affinity chromatography. The open reading frame of the pgCyP full-length coding sequence was found to encode a single-domain CyP-like protein of 174 amino residues with a calculated molecular weight of 18...
December 2017: Biomedical Reports
https://www.readbyqxmd.com/read/29186583/transcriptomic-analysis-of-kalopanax-septemlobus-and-characterization-of-ksbas-cyp716a94-and-cyp72a397-genes-involved-in-hederagenin-saponin-biosynthesis
#19
Jung Yeon Han, Ju-Hyeon Chun, Se A O, Seong-Bum Park, Hwan-Su Hwang, Hyoshin Lee, Yong Eui Choi
Kalopanax septemlobus, commonly named the castor aralia tree, is highly valued woody medicinal tree belonging to the family Araliaceae. K. septemlobus contains approximately 15 triterpenoid saponins primarily constituted with hederagenin aglycones. Hederagenin is a representative precursor for hemolytic saponin in plants. In the present study, transcriptome analysis was performed to discover genes involved in hederagenin saponin biosynthesis in K. septemlobus. De novo assembly generated 82,698 unique sequences, including 17,747 contigs and 64,951 singletons, following 454 pyrosequencing...
November 24, 2017: Plant & Cell Physiology
https://www.readbyqxmd.com/read/29185193/physical-exercise-promotes-memory-capability-by-enhancing-hippocampal-mitochondrial-functions-and-inhibiting-apoptosis-in-obesity-induced-insulin-resistance-by-high-fat-diet
#20
Hye-Sang Park, Han-Sam Cho, Tae-Woon Kim
A high-fat diet induces obesity in mice, leading to insulin resistance, decreased mitochondrial function, and increased apoptosis in the hippocampus, which eventually result in memory loss. The present study investigated the effect of physical exercise on memory, hippocampal mitochondrial function, and apoptosis in mice with in insulin resistance caused by obesity due to high-fat diet. Mice were randomly divided into four groups: control (CON), control and exercise (CON + EX), high fat diet (HFD), and high fat diet and exercise (HFD + EX)...
November 29, 2017: Metabolic Brain Disease
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