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https://www.readbyqxmd.com/read/29449808/suppressive-effects-of-clerodendrum-volubile-p-beauv-labiatae-methanolic-extract-and-its-fractions-on-type-2-diabetes-and-its-complications
#1
Ochuko L Erukainure, Rahman M Hafizur, Nurul Kabir, M Iqbal Choudhary, Olubunmi Atolani, Priyanka Banerjee, Robert Preissner, Chika I Chukwuma, Aliyu Muhammad, Eric O Amonsou, Md Shahidul Islam
Type 2 diabetes is the most prominent of all diabetes types, contributing to global morbidity and mortality. Availability and cost of treatment with little or no side effect especially in developing countries, remains a huge burden. This has led to the search of affordable alternative therapies especially from medicinal plants. In this study, the antidiabetic effect of the methanolic extract, dichloromethane (DCM), butanol (BuOH) and aqueous fractions of Clerodendrum volubile leaves were investigated in type 2 diabetic rats for their effect on glucose homeostasis, serum insulin level and hepatic biomarkers, lipid profile, pancreatic redox balance and Ca 2+ levels, and β-cell distribution and function...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29430676/metabolite-identification-of-the-antimalarial-naphthoquine-using-liquid-chromatography-tandem-high-resolution-mass-spectrometry-in-combination-with-multiple-data-mining-tools
#2
Yanhong Sun, Shuqi Wang, Jianbo Ji, Guangxi Zhai, Jie Xing
Naphthoquine (NQ) is one of important partner drugs of Artemisinin-based combination therapy (ACT), which is recommended for the treatment of uncomplicated Plasmodium falciparum. NQ shows a high cure rate after a single oral administration. It is absorbed quickly (Tmax 2-4 h) and has a long elimination half-life (255 h). However, the metabolism of NQ has not been clarified. In this work, the metabolite profiling of NQ was studied in six liver microsomal incubates (human, cynomolgus monkey, beagle dog, mini pig, rat and CD1 mouse), seven recombinant CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and rat (plasma, urine, bile and feces ) using liquid chromatography tandem high-resolution LTQ-Orbitrap mass spectrometry (HRMSn ) in conjunction with online H/D exchange...
February 12, 2018: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29421559/enrichment-of-high-functioning-human-ips-cell-derived-hepatocyte-like-cells-for-pharmaceutical-research
#3
Kazuo Takayama, Yasuko Hagihara, Yukiko Toba, Kiyotoshi Sekiguchi, Fuminori Sakurai, Hiroyuki Mizuguchi
Human iPS cell-derived hepatocyte-like cells are expected to be utilized in pharmaceutical research. However, the purity of high-functioning hepatocyte-like cells is not high enough. In particular, the purity of cytochrome P450 3A4 (CYP3A4), which is a representative hepatic drug-metabolizing enzyme, positive cells is still quite low (approximately 20%). To address this problem, we established the CYP3A4-NeoR-EGFP transgenic reporter human iPS cell line (CYP3A4-NeoR-EGFP iPS cells) by using genome editing technology...
January 18, 2018: Biomaterials
https://www.readbyqxmd.com/read/29420304/accurate-determination-of-the-cyp2d6-1-4-xn-genotype-by-quantitative-pcr
#4
Kirsten M Pondman, Ron H N van Schaik, Jan van der Weide
BACKGROUND: CYP2D6 is responsible for the metabolism of approximately 25% of all drugs. The expression of cytochrome P450 2D6 (CYP2D6) is influenced by a combination of factors including polymorphisms in the CYP2D6 gene. Analysis of the CYP2D6 genotype is used to personalize the medication to a patient's metabolism. Although many genotypes can be determined using standard genotype analysis, in some cases, an incomplete analysis is performed. The CYP2D6 genotype *1/*4 often occurs in combination with a multiplication of the CYP2D6 gene, and is reported as (*1/*4)xN...
February 8, 2018: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29414024/metabolism-of-flavonolignans-in-human-hepatocytes
#5
Jiří Vrba, Barbora Papoušková, Lenka Roubalová, Martina Zatloukalová, David Biedermann, Vladimír Křen, Kateřina Valentová, Jitka Ulrichová, Jan Vacek
This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry...
January 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29404931/genotyping-as-a-key-element-of-sample-size-optimization-in-bioequivalence-of-risperidone-tablets
#6
Ying Chen, Yang Deng, Miao Yan, Zhenyan Hou, Yao Li, Bikui Zhang, Hualin Cai
BACKGROUND AND OBJECTIVES: Risperidone is a derivative of benzisoxazole and is widely used for schizophrenia and other psychiatric illnesses in both adults and children. Previous studies have confirmed that it is a highly variable drug (within-subject variability ≥ 30%). To reduce the large sample size required for bioequivalence researches on highly variable drugs, a role for genotyping in the design of the bioequivalence study was employed. METHODS: A randomized, open-label, two-period crossover study was adopted: 20 subjects with specific genotypes carrying cytochrome P450 (CYP) 2D6*10 were randomized to two groups to receive a single oral dose of trial formulation or reference formulation with a 2-week washout period...
February 5, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29389842/dihydrocodeine-overdoses-in-a-neonate-and-in-a-14-year-old-girl-who-were-both-genotyped-as-cytochrome-p450-2d6-1-10-36-comparing-developmental-ages-and-drug-monitoring-data-with-the-results-of-pharmacokinetic-modeling
#7
Makiko Shimizu, Tatsuki Kondo, Tetsuya Fukuoka, Toshihiro Tanaka, Hiroshi Yamazaki
A high activity of cytochrome P450 2D6 (CYP2D6) reportedly leads toxicity of dihydrocodeine/codeine by increasing toxic potential of their metabolite dihydromorphine/morphine, which are further metabolized to highly active dihydromorphine 6-O-glucuronide and the less active morphine 3-O-glucorinide but rapidly excreted into urine as water-soluble forms. A case of acute respiratory depression after administration of prescribed dihydrocodeine phosphate (2.0 mg/day divided TID for 2 days) to a 1-month-old baby boy genotyped as cytochrome CYP2D6*1/*10-*36 is described...
January 30, 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29374135/sulfenylation-of-human-liver-and-kidney-microsomal-cytochromes-p450-and-other-drug-metabolizing-enzymes-as-a-response-to-redox-alteration
#8
Matt Albertolle, Thanh T N Phan, Ambra Pozzi, F Peter Guengerich
The lumen of the endoplasmic reticulum (ER) provides an oxidizing environment to aid in the formation of disulfide bonds, which is tightly regulated by both antioxidant proteins and small molecules. On the cytoplasmic side of the ER, cytochrome P450 (P450) proteins have been identified as a superfamily of enzymes that are important in the formation of endogenous chemicals as well as in the detoxication of xenobiotics. Our previous report described oxidative inhibition of P450 Family 4 enzymes via oxidation of the heme-thiolate cysteine to a sulfenic acid (-SOH) (Albertolle, M...
January 26, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29369497/pharmacogenetics-of-risperidone-induced-insulin-resistance-in-children-and-adolescents-with-autism-spectrum-disorder
#9
Chonlaphat Sukasem, Natchaya Vanwong, Pornpen Srisawasdi, Nattawat Ngamsamut, Nopphadol Nuntamool, Yaowaluck Hongkaew, Apichaya Puangpetch, Bhunnada Chamkrachangpada, Penkhae Limsila
The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body weight and height. Genotyping was performed by Taqman real-time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852), and *41 (rs28371725), ATP-binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642), and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag-SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) -2548G>A (rs7799039), ghrelin gene (GHRL) -604G>A (rs27647), and brain-derived neurotrophic factor (BDNF) 196G>A (rs6265)...
January 25, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29357870/primaquine-ineligibility-in-anti-relapse-therapy-of-plasmodium-vivax-malaria-the-problem-of-g6pd-deficiency-and-cytochrome-p-450-2d6-polymorphisms
#10
EDITORIAL
J Kevin Baird, Katherine E Battle, Rosalind E Howes
The hypnozoite reservoir of Plasmodium vivax represents both the greatest obstacle and opportunity for ultimately eradicating this species. It is silent and cannot be diagnosed until it awakens and provokes a clinical attack with attendant morbidity, risk of mortality, and opportunities for onward transmission. The only licensed drug that kills hypnozoites is primaquine, which attacks the hypnozoite reservoir but imposes serious obstacles in doing so-at hypnozoitocidal doses, it invariably causes a threatening acute haemolytic anaemia in patients having an inborn deficiency in glucose-6-phosphate dehydrogenase (G6PD), affecting about 8% of people living in malaria endemic nations...
January 22, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29338933/physiological-based-pharmacokinetic-modeling-to-estimate-in%C3%A2-vivo-ki-of-ketoconazole-on-renal-p-gp-using-human-drug-drug-interaction-study-result-of-fesoterodine-and-ketoconazole
#11
Masayo Oishi, Yuma Takano, Yutaka Torita, Bimal Malhotra, Koji Chiba
This study was conducted to estimate in vivo inhibition constant (Ki) of ketoconazole on renal P-glycoprotein (P-gp) using human drug-drug interaction (DDI) study result of fesoterodine and ketoconazole. Fesoterodine is a prodrug which is extensively hydrolyzed by non-specific esterases to the active metabolite 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is then further metabolized via Cytochrome P450 (CYP) 2D6 and CYP3A4. It is reported that 5-HMT is a substrate of P-gp whereas fesoterodine is not. Renal clearance of 5-HMT is approximately two-times greater than renal glomerular filtration rate...
November 15, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29336270/in-silico-ligand-based-identification-of-novel-acetylcholinesterase-inhibitors-against-alzheimer-s-disease-ad
#12
Mohammad Usman Mirza, Nazia Ikram, Nauman Mazhar, Kanzal Iman, Mehwish Riaz, Mohammad A Kamal
Alzheimer disease (AD) is a hot research topic currently across the world, characterized by the formation of β-amyloid plaques and neurofibrillary tangles. Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site (PAS) as an allosteric regulator of AChE. Progression of this neurodegenerative disorder causes a deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function...
January 15, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/29329342/ternary-copper-ii-complex-nci60-screening-toxicity-studies-and-evaluation-of-efficacy-in-xenograft-models-of-nasopharyngeal-carcinoma
#13
Munirah Ahmad, Shazlan-Noor Suhaimi, Tai-Lin Chu, Norazlin Abdul Aziz, Noor-Kaslina Mohd Kornain, D S Samiulla, Kwok-Wai Lo, Chew-Hee Ng, Alan Soo-Beng Khoo
Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4...
2018: PloS One
https://www.readbyqxmd.com/read/29325225/influence-of-cyp2d6-cyp3a4-cyp3a5-and-abcb1-polymorphisms-on-pharmacokinetics-and-safety-of-aripiprazole-in-healthy-volunteers
#14
Carmen Belmonte, Dolores Ochoa, Manuel Román, Miriam Saiz-Rodríguez, Aneta Wojnicz, Clara Isabel Gómez-Sánchez, Samuel Martín-Vilchez, Francisco Abad-Santos
The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from 6 bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined...
January 11, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29324864/safety-of-single-low-dose-primaquine-in-glucose-6-phosphate-dehydrogenase-deficient-falciparum-infected-african-males-two-open-label-randomized-safety-trials
#15
Guido J H Bastiaens, Alfred B Tiono, Joseph Okebe, Helmi E Pett, Sam A Coulibaly, Bronner P Gonçalves, Muna Affara, Alphonse Ouédraogo, Edith C Bougouma, Guillaume S Sanou, Issa Nébié, John Bradley, Kjerstin H W Lanke, Mikko Niemi, Sodiomon B Sirima, Umberto d'Alessandro, Teun Bousema, Chris Drakeley
BACKGROUND: Primaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria. METHODS AND FINDINGS: In Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0...
2018: PloS One
https://www.readbyqxmd.com/read/29291439/novel-non-sulfonamide-5-ht6-receptor-partial-inverse-agonist-in-a-group-of-imidazo-4-5-b-pyridines-with-cognition-enhancing-properties
#16
David Vanda, Miroslav Soural, Vittorio Canale, Séverine Chaumont-Dubel, Grzegorz Satała, Tomasz Kos, Petr Funk, Veronika Fülöpová, Barbora Lemrová, Paulina Koczurkiewicz, Elżbieta Pękala, Andrzej J Bojarski, Piotr Popik, Philippe Marin, Paweł Zajdel
A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT6 receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT6 receptor partial inverse agonist in Gs signaling (Ki = 6 nM, IC50 = 17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects...
December 16, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29258368/lisdexamfetamine-chemistry-pharmacodynamics-pharmacokinetics-and-clinical-efficacy-safety-and-tolerability-in-the-treatment-of-binge-eating-disorder
#17
Kristen Ward, Leslie Citrome
The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED). Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the clinical trials investigating the efficacy and safety of this medication for the management of BED. Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for the treatment of BED. It is an inactive prodrug of d-amphetamine that extends the half-life of d-amphetamine to allow for once daily dosing...
February 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29247736/metabolic-pathway-of-icotinib-in-vitro-the-differential-roles-of-cyp3a4-cyp3a5-and-cyp1a2-on-potential-pharmacokinetic-drug-drug-interaction
#18
TianHong Zhang, KeRong Zhang, Li Ma, Zheng Li, Juan Wang, YunXia Zhang, Chuang Lu, MingShe Zhu, XiaoMei Zhuang
Icotinib is the self-developed small molecule drug in China for targeted therapy of non-small-cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction (DDI) of icotinib were limited. By identifying metabolite generation in human liver microsomes (HLM) and revealing the contributions of major CYPs in the formation of major metabolites, the aim of the present work is to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A LC/UV/HRMS method was developed to characterize the icotinib metabolites...
December 13, 2017: Journal of Pharmaceutical Sciences
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
#19
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
#20
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
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