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Marie Daugan, Amélie Dufaÿ Wojcicki, Benoit d'Hayer, Vincent Boudy
Since epidemiologic data have highlighted the positive effects of metformin to reduce cancer incidence and mortality, many in vitro and in vivo studies as well as a large number of clinical trials have been conducted in order to study its potential. The many anticancer actions of metformin lead to a cytostatic effect. Two distinct but not exclusive mechanisms can be implicated in these actions. First, by decreasing insulinemia and glycaemia, metformin can block the PI3K/MAPK signalling pathway implicated in cell growth...
October 5, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Cornelius Kürten, Mladen Tzvetkov, Volker Ellenrieder, Harald Schwörer
History and clinical findings | We report about a 79 year old non-diabetic patient who was admitted to the emergency room with severe hypoglycemia (blood glucose level: 36 mg / dl and Glasgow Coma Scale Score: 3). After the infusion of G40 % her blood glucose level stabilised. The patient reported to have taken 50 mg of Tramadol during the night to treat her headache. Investigations and diagnosis | No other differential diagnosis for hypoglycemia (i.e. diabetes, insulinoma, severe liver or kidney disease) could be established...
September 2016: Deutsche Medizinische Wochenschrift
Staci L Haney, G Michael Upchurch, Jana Opavska, David Klinkebiel, Ryan A Hlady, Sohini Roy, Samikshan Dutta, Kaustubh Datta, Rene Opavsky
DNA methyltransferase 3A (DNMT3A) is an enzyme involved in DNA methylation that is frequently mutated in human hematologic malignancies. We have previously shown that inactivation of Dnmt3a in hematopoietic cells results in chronic lymphocytic leukemia in mice. Here we show that 12% of Dnmt3a-deficient mice develop CD8+ mature peripheral T cell lymphomas (PTCL) and 29% of mice are affected by both diseases. 10% of Dnmt3a+/- mice develop lymphomas, suggesting that Dnmt3a is a haploinsufficient tumor suppressor in PTCL...
September 2016: PLoS Genetics
Alex McCormick, Helen Swaisland
1. In vitro assessments were conducted to examine interactions between olaparib (a potent oral inhibitor of poly[ADP-ribose] polymerase) and drug transporters. 2. Olaparib showed inhibition of the hepatic drug uptake transporters OATP1B1 (IC50 values of 20.3 μM and 27.1 μM) and OCT1 (IC50 37.9 μM), but limited inhibition of OATP1B3 (25% at 100 µM); inhibition of the renal uptake transporters OCT2 (IC50 19.9 μM) and OAT3 (IC50 18.4 μM), but limited inhibition of OAT1 (13.5% at 100 µM); inhibition of the renal efflux transporters MATE1 and MATE2K (IC50s 5...
September 29, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Jiayin Chen, Jürgen Brockmöller, Tina Seitz, Jörg König, Xijing Chen, Mladen V Tzvetkov
Tropane alkaloids and their derivatives are anticholinergic drugs with narrow therapeutic range. Here we characterize the organic cation transporters from the SLC22 (OCT1, OCT2, and OCT3) and the SLC47 families (MATE1 and MATE2-K) as potential mediators of the renal and extra-renal excretion, the two major roads of elimination of these substances. All analyzed compounds inhibited and the quaternary amine derivatives ipratropium and trospium were strongly transported by OCTs and MATEs. Overexpression of OCTs or MATEs in HEK293 cells resulted in up to 63-fold increase in the uptake of ipratropium (Km of 0...
September 27, 2016: Biological Chemistry
Lindsey H M Te Brake, Jeroen J M W van den Heuvel, Aaron Ohene Buaben, Reinout van Crevel, Albert Bilos, Frans G Russel, Rob E Aarnoutse, Jan B Koenderink
INTRODUCTION: It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). Thus any DDIs would primarily be mediated via these transporters. This study aimed to assess the in vitro inhibitory effects of TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin and linezolid) on metformin transport, and whether TB drugs are also substrates themselves of OCTs and MATEs...
September 19, 2016: Antimicrobial Agents and Chemotherapy
Marcia Cristina Dias de Moraes, Anderson Zanardi Freitas, Ana Cecilia Correa Aranha
This study aimed to use optical coherence tomography (OCT) to assess the progression of erosive lesions after irradiation with Nd:YAG laser and application of topical fluoride. One-hundred and twenty dentin samples (4 × 4 × 2 mm) obtained from bovine incisors were used. Samples were protected with acid-resistant nail varnish, with exception of a central circular area 2 mm in diameter. All samples were submitted to erosive cycles with citric acid solution 0.05 M (citric acid monohydrate-C6H8O7·H2O); M = 210...
September 17, 2016: Lasers in Medical Science
S Harrach, C Schmidt-Lauber, T Pap, H Pavenstädt, E Schlatter, E Schmidt, W E Berdel, U Schulze, B Edemir, S Jeromin, T Haferlach, G Ciarimboli, J Bertrand
Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25-30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity...
2016: Blood Cancer Journal
Chun-Hong Shen, Yin-Xi Zhang, Ru-Yi Lu, Bo Jin, Shan Wang, Zhi-Rong Liu, Ye-Lei Tang, Mei-Ping Ding
PURPOSE: The pharmacokinetics of Lamotrigine (LTG) varies widely among patients with epilepsy. In this study, we are aiming to investigate the effects of OCT1, ABCG2, ABCC2 and HNF4α genetic polymorphisms on plasma LTG concentrations and therapeutic efficacy in Chinese patients with epilepsy. METHODS: The study cohort comprised 112 Han Chinese patients with epilepsy who were receiving LTG monotherapy. Blood samples were taken and LTG levels were measured. The polymorphisms of OCT1 rs2282143, rs628031, ABCG2 rs2231142, rs2231137, ABCC2 rs2273697 and HNF4α rs2071197, rs3212183 were determined...
September 1, 2016: Epilepsy Research
Ryota Kikuchi, Vincent C Peterkin, William J Chiou, Sonia M de Morais, Daniel A J Bow
1. Accurate predictions of clinical transporter-mediated drug-drug interactions (DDI) from in vitro data can be challenging when compounds have poor solubility and/or high nonspecific binding. Additionally, current DDI predictions for compounds with high plasma-protein binding assume that the unbound fraction in plasma is 0.01, if the experimental value is less than 0.01 or cannot be determined. This approach may result in an overestimation of DDI risk. To overcome these challenges, it may be beneficial to conduct inhibition studies under physiologically relevant conditions...
October 3, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Yagmur Yagdiran, Jonas Tallkvist, Karin Artursson, Agneta Oskarsson
Inflammation in the mammary gland (mastitis) is the most common disease in dairy herds worldwide, often caused by the pathogens Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Little is known about the effects of mastitis on drug transporters and the impact on transporter-mediated excretion of drugs into milk. We used murine mammary epithelial HC11 cells, after lactogenic differentiation into a secreting phenotype, and studied gene expressions of ABC- and SLC- transporters after treatment of cells with S...
2016: PloS One
Md Masud Parvez, Nazia Kaisar, Ho Jung Shin, Jin Ah Jung, Jae-Gook Shin
Currently marketed 22 anti-tuberculosis drugs were comprehensively evaluated for the inhibitory effect on organic anionic (OAT) and cation transporter (OCT)-mediated uptake using stably transfected HEK293 cells in vitro We observed moderate to strong inhibitory effects on OAT1-, OAT3-mediated para-aminohippurate (PAH) and OCT1- and OCT2-mediated N-methyl-4-phenylpylidinium acetate (MPP(+)) uptake. The strong inhibitory effect was observed by ciprofloxacin, linezolid, para-aminosalicylic acid (PAS) and rifampin with IC50 values 35...
August 22, 2016: Antimicrobial Agents and Chemotherapy
Li Wang, Carol Collins, Edward J Kelly, Xiaoyan Chu, Adrian S Ray, Laurent Salphati, Guangqing Xiao, Caroline Lee, Yurong Lai, Mingxiang Liao, Anita Mathias, Raymond Evers, William Humphreys, Cornelis E C A Hop, Sean C Kumer, Jashvant D Unadkat
Although data are available on the change of expression/activity of drug-metabolizing enzymes in liver cirrhosis patients, corresponding data on transporter protein expression are not available. Therefore, using quantitative targeted proteomics, we compared our previous data on noncirrhotic control livers (n = 36) with the protein expression of major hepatobiliary transporters, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion protein 1 (MATE1), multidrug resistance-associated protein (MRP)2, MRP3, MRP4, sodium taurocholate-cotransporting polypeptide (NTCP), organic anion-transporting polypeptides (OATP)1B1, 1B3, 2B1, organic cation transporter 1 (OCT1), and P-glycoprotein (P-gp) in alcoholic (n = 27) and hepatitis C cirrhosis (n = 30) livers...
November 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
A Salem, S Rozov, A Al-Samadi, V Stegajev, D Listyarifah, V-P Kouri, X Han, D Nordström, J Hagström, K Eklund
BACKGROUND: Recent reports indicated that non-immune cells can produce low concentrations of histamine. This observation together with the discovery of the high-affinity histamine H4 receptor (H4 R) has added additional layers of complexity to our understanding of histamine signalling. Human oral keratinocytes (HOKs) possess a uniform H4 R-pattern which is deranged in oral lichen planus (OLP). OBJECTIVES: To investigate histamine metabolism and transport in HOKs of healthy controls and OLP patients...
August 20, 2016: British Journal of Dermatology
Ulrike M Stamer, Frank Musshoff, Frank Stüber, Jürgen Brockmöller, Michael Steffens, Mladen V Tzvetkov
The organic cation transporter OCT1 (SLC22A1) mediates uptake and metabolism of the active tramadol metabolite (+)O-desmethyltramadol in the liver. In this study, the influence of OCT1 genetic polymorphisms on pharmacokinetics and analgesic efficacy of tramadol in patients recovering from surgery was analyzed in addition to the CYP2D6 genotype. Postoperative patients who received tramadol through patient-controlled analgesia were enrolled. Genotypes resulting in 0, 1, or 2 active OCT1 alleles were determined as well as CYP2D6 genotypes...
November 2016: Pain
Ming Wang, Jing Zhao, Nan Zhang, Jianghua Chen
Astilbin is a flavonoid compound derived from the rhizome of Smilax china L. The effects and possible molecular mechanisms of astilbin on potassium oxonate-induced hyperuricemia mice were investigated in this study. Different dosages of astilbin (5, 10, and 20mg/kg) were administered to induce hyperuricemic mice. The results demonstrated that the serum uric acid (Sur) level was significantly decreased by increasing the urinary uric acid (Uur) level and fractional excretion of urate (FEUA) with astilbin, related with suppressing role in meditation of Glucose transporter 9 (GLUT9), Human urate transporter 1 (URAT1) expression and up-regulation of ABCG2, Organic anion transporter 1/3 (OAT1/3) and Organic cation transporter 1 (OCT1)...
August 11, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Ivan Mihaljevic, Marta Popovic, Roko Zaja, Tvrtko Smital
BACKGROUND: SLC22 protein family is a member of the SLC (Solute carriers) superfamily of polyspecific membrane transporters responsible for uptake of a wide range of organic anions and cations, including numerous endo- and xenobiotics. Due to the lack of knowledge on zebrafish Slc22 family, we performed initial characterization of these transporters using a detailed phylogenetic and conserved synteny analysis followed by the tissue specific expression profiling of slc22 transcripts. RESULTS: We identified 20 zebrafish slc22 genes which are organized in the same functional subgroups as human SLC22 members...
2016: BMC Genomics
Sara Neyt, Maarten Vliegen, Bjorn Verreet, Stef De Lombaerde, Kim Braeckman, Christian Vanhove, Maarten Thomas Huisman, Caroline Dumolyn, Ken Kersemans, Fabian Hulpia, Serge Van Calenbergh, Geert Mannens, Filip De Vos
INTRODUCTION: Hepatobiliary transport mechanisms are crucial for the excretion of substrate toxic compounds. Drugs can inhibit these transporters, which can lead to drug-drug interactions causing toxicity. Therefore, it is important to assess this early during the development of new drug candidates. The aim of the current study is the (radio)synthesis, in vitro and in vivo evaluation of a technetium labeled chenodeoxycholic and cholic acid analogue: [(99m)Tc]-DTPA-CDCA and [(99m)]Tc-DTPA-CA, respectively, as biomarker for disturbed transporter functionality...
October 2016: Nuclear Medicine and Biology
Rong Wang, Chun-Hua Ma, Fan Zhou, Ling-Dong Kong
The aim of the study was to investigate the effects of Siwu decoction on hyperuricemia, kidney inflammation, and dysfunction in hyperuricemic mice. Siwu decoction at 363.8, 727.5, and 1 455 mg·kg(-1) was orally administered to potassium oxonate-induced hyperuricemic mice for 7 days. Serum urate, creatinine, and blood urea nitrogen levels and hepatic xanthine oxidase (XOD) activity were measured. The protein levels of hepatic XOD and renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), ATP-binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), OCT2, organic cation/carnitine transporter 1 (OCTN1), OCNT2, Nod-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), Caspase-1, and interleukin-1β (IL-1β) were determined by Western blotting...
July 2016: Chinese Journal of Natural Medicines
Andrea Hubeny, Markus Keiser, Stefan Oswald, Gabriele Jedlitschky, Heyo K Kroemer, Werner Siegmund, Markus Grube
Important antimalarial drugs, including quinolines, act against blood schizonts by interfering with hemoglobin metabolism. To reach their site of action, these compounds have to cross the plasma membrane of red blood cells (RBCs). Organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) are important uptake transporters and interesting candidates for local drug transport. We therefore studied their interaction with antimalarial compounds (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate) and characterized the expression of OATP1A2 and OATP2B1 in RBCs...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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