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Begüm Nurpelin Sağlık, Sinem Ilgın, Yusuf Özkay
Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1-38) were elucidated by IR, (1)H NMR, (13)C NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme...
October 19, 2016: European Journal of Medicinal Chemistry
Daniella Kovacsics, Izabel Patik, Csilla Özvegy-Laczka
The in vivo fate and effectiveness of a drug depends highly on its absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Organic anion transporting polypeptides (OATPs) are membrane proteins involved in the cellular uptake of various organic compounds, including clinically used drugs. Since OATPs are significant players in drug absorption and distribution, modulation of OATP function via pharmacotherapy with OATP substrates/inhibitors, or modulation of their expression, affects drug pharmacokinetics...
October 26, 2016: Expert Opinion on Drug Metabolism & Toxicology
Mira Tout, Anne-Laure Gagez, Stéphane Leprêtre, Valérie Gouilleux-Gruart, Nicolas Azzopardi, Alain Delmer, Mélanie Mercier, Loïc Ysebaert, Kamel Laribi, Hugo Gonzalez, Gilles Paintaud, Guillaume Cartron, David Ternant
BACKGROUND AND OBJECTIVES: Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcγRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL. METHODS: Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance...
October 25, 2016: Clinical Pharmacokinetics
Takao Saito, Masayuki Iwano, Koichi Matsumoto, Tetsuya Mitarai, Hitoshi Yokoyama, Noriaki Yorioka, Shinichi Nishi, Ashio Yoshimura, Hiroshi Sato, Satoru Ogahara, Yoshie Sasatomi, Yasufumi Kataoka, Shiro Ueda, Akio Koyama, Shoichi Maruyama, Masaomi Nangaku, Enyu Imai, Seiichi Matsuo, Yasuhiko Tomino
BACKGROUND: We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS). METHODS: Patients with IMN were divided into 2 groups, and MZR combined with PSL was administered for 2 years. PSL was initially prescribed at 40 mg/day and tapered. MZR was given once-a-day at 150 mg and 3-times-a-day at 50 mg each to groups 1 and 2...
October 25, 2016: Clinical and Experimental Nephrology
May Garrett, Timothy Taylor, Diane R Mould, Michael A Amantea, Ying Chen, Antonella Ingrosso, Yazdi K Pithavala
PURPOSE: Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers. METHODS: Data were pooled from six clinical studies-serial pharmacokinetics from two healthy volunteer studies (n = 58) and sparse pharmacokinetics from four NSCLC studies (n = 152)-for a nonlinear mixed effects modeling (NONMEM v7...
October 25, 2016: Cancer Chemotherapy and Pharmacology
Nicholas M Dalesio, Craig W Hendrix, Douglas Hale McMichael, Carol B Thompson, Carlton K K Lee, Huy Pho, Rafael S Arias, Rachael Rzasa Lynn, Jeffrey Galinkin, Myron Yaster, Robert H Brown, Alan R Schwartz
BACKGROUND: Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. METHODS: Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy...
October 24, 2016: Anesthesia and Analgesia
Madhav P Yadav, Sanjana Ballal, Madhavi Tripathi, Nishikant A Damle, Ranjit K Sahoo, Amlesh Seth, Chandrasekhar Bal
OBJECTIVE: Lu-DKFZ-PSMA-617, a urea-based compound, binds to the extracellular domain of prostate-specific membrane antigen, thus providing an effective target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Before its therapeutic use, it is necessary that the radiation dosimetry of this radiopharmaceutical be studied to determine the safe activity that can be administered in patients to prevent haematological, renal and liver toxicity. The present study thus aimed to assess the pharmacokinetics and dosimetry of Lu-DKFZ-PSMA-617 in CRPC patients...
October 25, 2016: Nuclear Medicine Communications
Michael A Lee, Naveed Bakh, Gili Bisker, Emery N Brown, Michael S Strano
Cortisol is an important glucocorticoid hormone whose biochemistry influences numerous physiological and pathological processes. Moreover, it is a biomarker of interest for a number of conditions, including posttraumatic stress disorder, Cushing's syndrome, Addison's disease, and others. An implantable biosensor capable of real time monitoring of cortisol concentrations in adipose tissue may revolutionize the diagnosis and treatment of these disorders, as well as provide an invaluable research tool. Toward this end, a mathematical model, informed by the physiological literature, is developed to predict dynamic cortisol concentrations in adipose, muscle, and brain tissues, where a significant number of important processes with cortisol occur...
October 26, 2016: Advanced Healthcare Materials
Rita Turnaturi, Giuseppina Aricò, Giuseppe Ronsisvalle, Lorella Pasquinucci, Carmela Parenti
Polypharmacology, or the associations between two or more drugs producing biological effects on two or more different sites of action could represent a possible therapeutic approach for the clinical management of acute and chronic pain. The multitude and complexity of neuronal mechanisms that contribute to pain transmission provide several possible targets for pharmacological intervention. Thus, multitarget ligands possessing opioid-opioid or non-opioid-opioid mechanisms of action are potential drug candidates for pain relief...
October 24, 2016: Current Medicinal Chemistry
So Miyoshi, Judith Hey-Hadavi, Makoto Nagaoka, Brinda Tammara
OBJECTIVE: Fosdagrocorat (PF-04171327) is a pro-drug form of PF-00251802, a dissociated agonist of the glucocorticoid receptor, under investigation for the treatment of rheumatoid arthritis. This study investigates the pharmacokinetics (PK) of single and multiple doses of fosdagrocorat in healthy Japanese and Western volunteers, the effect of food on fosdagrocorat PK, and the effect of fosdagrocorat on bone biomarkers. METHODS: This was a phase 1, randomized, placebo-controlled, dose-escalation study...
October 26, 2016: International Journal of Clinical Pharmacology and Therapeutics
Yuka Terada, Kyoichi Wada, Sachi Matsuda, Takeshi Kuwahara, Atsufumi Kawabata, Mitsutaka Takada, Takuya Watanabe, Seiko Nakajima, Takuma Sato, Osamu Seguchi, Masanobu Yanase, Norihide Fukushima, Takeshi Nakatani
OBJECTIVE: To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentration-time curve (AUC) of EVL in heart transplant patients. METHODS: Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C0), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL...
October 26, 2016: International Journal of Clinical Pharmacology and Therapeutics
Simone Hansmann, Adam Darwich, Alison Margolskee, Leon Aarons, Jennifer Dressman
OBJECTIVES: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success. METHODS: Simcyp Simulator, GastroPlus(™) and GI-Sim were used. Compounds with published Biowaiver monographs (bisoprolol (BCS I), nifedipine (BCS II), cimetidine (BCS III), furosemide (BCS IV)) were selected to ensure availability of accurate and reproducible data for all required parameters...
October 26, 2016: Journal of Pharmacy and Pharmacology
Nikolaos Karamichalakis, Stamatis Georgopoulos, Konstantinos Vlachos, Ioannis Liatakis, Michael Efremidis, Antonios Sideris, Konstantinos P Letsas
Atrial fibrillation and venous thromboembolism (VTE) are common disorders associated with maleficent thrombotic events, particularly in the elderly patients. Polypharmacy, co-morbidities, and altered pharmacokinetics, often present in these patients, render the use of anticoagulants quite challenging. Novel oral anticoagulants (NOACs) have recently emerged as alternatives to Vitamin K Antagonists (VKAs) and are gradually increasing their popularity mainly because of their fewer drug and food interactions and ease of use...
August 2016: Journal of Geriatric Cardiology: JGC
Joshua J Gagne, Nazleen F Khan, Tara S Raj, Lajja R Patel, Niteesh K Choudhry
BACKGROUND/AIMS: Renally excreted medications often require dose adjustment in patients with kidney impairment. While drug development and approval in the United States are typically based on several Phase I and II studies and one or more larger Phase III randomized trials, the basis for labeled dosing recommendations for patients with renal impairment is less well known. In response, we aimed to quantify the level of evidence used to recommend labeled dosing adjustments for newly approved drugs in patients with renal impairment...
October 24, 2016: Clinical Trials: Journal of the Society for Clinical Trials
Meredith K Chuk, Yeruk Mulugeta, Michelle Roth-Cline, Nitin Mehrotra, Gregory H Reaman
The enrollment of adolescents with cancer in clinical trials is much lower than younger pediatric patients. For adolescents with "adult-type" cancers, lack of access to relevant trials is cited as one of the reasons for this discrepancy. Adolescents are generally not eligible for enrollment on adult oncology trials, and initial pediatric trials for many drugs are conducted years later, often after the drug is approved. As a result, accrual of adolescents to these trials may be slow due to off-label use, prospectively collected safety and efficacy data is lacking at the time of initial approval, and, most importantly, these adolescents have delayed access to effective therapies...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
John T Randolph, Charles A Flentge, Pamela Donner, Todd W Rockway, Sachin V Patel, Lissa Nelson, Douglas K Hutchinson, Rubina Mondal, Neeta Mistry, Thomas Reisch, Tatyana Dekhtyar, Preethi Krishnan, Tami Pilot-Matias, Deanne F Stolarik, David W A Beno, Rolf Wagner, Clarence Maring, Warren M Kati
Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series...
October 13, 2016: Bioorganic & Medicinal Chemistry Letters
Josef Reznicek, Martina Ceckova, Lenka Tupova, Frantisek Staud
INTRODUCTION: All HIV positive pregnant women should receive combination antiretroviral therapy (cART) to prevent mother-to-child transmission (MTCT) of the virus. It has recently been shown that fetal exposure of nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and abacavir is decreased by placental ABC transporters p-glycoprotein (ABCB1) and BCRP (ABCG2). The aim of this study was to evaluate transporter-mediated drug-drug interactions (DDI) between etravirine (TMC125), a novel non-nucleoside reverse transcriptase inhibitor used in cART, and the NRTIs and to assess the relevance of such DDI for transplacental pharmacokinetics of TDF and abacavir...
November 2016: Placenta
Virginie Avrillon, Maurice Pérol
Alectinib is a highly selective second-generation ALK inhibitor that is active against most crizotinib ALK resistance mutations, with a good penetration in CNS and a good safety profile. Thanks to the positive results of Phase II trials, alectinib was approved in Japan and by the US FDA for ALK-positive non-small-cell lung cancer (NSCLC) patients pretreated with crizotinib. Recently, the Phase III J-ALEX study demonstrated superiority of alectinib over crizotinib in crizotinib naive ALK-positive NSCLC, with an impressive improvement of progression-free survival...
October 26, 2016: Future Oncology
Merja Kokki, Marja Heikkinen, Pyry Välitalo, Heidi Hautajärvi, Juho Hokkanen, Hanna Pitkänen, Ulla Sankilampi, Veli-Pekka Ranta, Hannu Kokki
BACKGROUND AND OBJECTIVES: This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2-year old infants. METHODS: Seventy-nine infants (gestational age 23-42 weeks; postnatal age 0-650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg/kg during or after surgery. Three to seven blood samples were taken from each infant, and plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were quantified...
October 25, 2016: British Journal of Clinical Pharmacology
Lenneke Schrier, Rob Zuiker, Frans W H M Merkus, Erica S Klaassen, Zheng Guan, Bert Tuk, Joop M A van Gerven, Ronald van der Geest, Geert Jan Groeneveld
AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (Saccadic Peak Velocity, the Bond and Lader Visual Analogue Scale for sedation, the Simple Reaction Time Task and the Observer's Assessment of Alertness/Sedation)...
October 25, 2016: British Journal of Clinical Pharmacology
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