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Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
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
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
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
Lena Tan, Elsa Taylor, Jacqueline A Hannam, Lesley Salkeld, Sam Salman, Brian J Anderson
BACKGROUND: Few pharmacokinetic (PK) and pharmacodynamic (PD) data exist for COX-2 selective inhibitors in children. We wished to characterize the PKPD of parecoxib and its active metabolite, valdecoxib, in this population. METHODS: Children (n = 59) were randomized to parecoxib 0.25 mg·kg(-1) , 1 mg·kg(-1) , and 2 mg·kg(-1) during tonsillectomy ± adenoidectomy. Samples (4-6 per child) were obtained from indwelling cannula over 6 h. A second group of inpatient children (n = 15) given 1 mg·kg(-1) contributed PK data from 6 to 24 h...
October 25, 2016: Paediatric Anaesthesia
S A Harrison, S R Marri, N Chalasani, R Kohli, W Aronstein, G A Thompson, W Irish, M V Miles, S A Xanthakos, E Lawitz, M Noureddin, T D Schiano, M Siddiqui, A Sanyal, B A Neuschwander-Tetri, P G Traber
BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis...
October 24, 2016: Alimentary Pharmacology & Therapeutics
Arshag D Mooradian
The availability of effective drugs targeting the major risk factors of cardiovascular disease (CVD) has reduced morbidity and mortality. Cumulative relative risk of CVD events can be reduced by 75 % with a combination of aspirin, a β-adrenoceptor antagonist (β-blocker), an HMG-CoA reductase inhibitor (statin), and an angiotensin-converting enzyme inhibitor. The principal pharmacodynamics of these drugs cannot explain the entirety of their cardioprotective action, as other drugs with similar pharmacologic targets have not been associated with favorable clinical effects...
October 24, 2016: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
F Sörgel, R Höhl, R Glaser, C Stelzer, M Munz, M Vormittag, M Kinzig, J Bulitta, C Landersdorfer, A Junger, M Christ, M Wilhelm, U Holzgrabe
Optimized dosage regimens of antibiotics have remained obscure since their introduction. During the last two decades pharmacokinetic(PK)-pharmacodynamic(PD) relationships, originally established in animal experiments, have been increasingly used in patients. The action of betalactams is believed to be governed by the time the plasma concentration is above the minimum inhibitory concentration (MIC). Aminoglycosides act as planned when the peak concentration is a multiple of the MIC and vancomycin seems to work best when the area under the plasma vs...
October 24, 2016: Medizinische Klinik, Intensivmedizin und Notfallmedizin
Flavio Egger, Federica Targa, Ivan Unterholzner, Russell P Grant, Markus Herrmann, Christian J Wiedermann
Non-vitamin K oral anticoagulant (NOAC) therapy may be inappropriate if prescription was incorrect, the patient's physiological parameters change, or interacting concomitant medications are erroneously added. The aim of this report was to illustrate inappropriate NOAC prescription in a 78-year-old woman with non-valvular atrial fibrillation and borderline renal dysfunction who was switched from warfarin to rivaroxaban and subsequently developed bruising with hemorrhagic shock and acute on chronic renal failure...
August 8, 2016: Clinics and Practice
Ekaterina S Dolinina, Elena V Parfenyuk
BACKGROUND: Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of efficient ways of improvement of pharmacological and consumer properties of drugs is development of optimal drug delivery systems. OBJECTIVE: The aim of this work is synthesis of novel warfarin - silica composites and study in vitro the drug release kinetics to obtain the composites with controlled release. METHODS: The composites of warfarin with unmodified (UMS) and mercaptopropy modified silica (MPMS) were synthesized by sol-gel method...
October 21, 2016: Current Drug Delivery
Ann W McMahon, Kevin Watt, Jian Wang, Dionna Green, Ram Tiwari, Gilbert J Burckart
BACKGROUND: Pediatric drug development is plagued by small sample sizes, unvalidated clinical endpoints, and limited studies. OBJECTIVES: The objective of this study was to determine whether age stratification within the pediatric population could be used to (1) assess response to a pharmacologic intervention and to (2) design future trials based upon published stratified disease data using clinical trial simulation (CTS). METHODS: Data available from the literature for Kawasaki disease (KD) was used in the model...
2016: Therapeutic Innovation & Regulatory Science
Yang Yu, Yu-Feng Zhou, Xiao Li, Mei-Ren Chen, Gui-Lin Qiao, Jian Sun, Xiao-Ping Liao, Ya-Hong Liu
This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 μg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened...
2016: Frontiers in Microbiology
Meredith C Fidler, Jack Beusmans, Paul Panorchan, Frederick Van Goor
Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor...
October 20, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Justin R Lenhard, Jonathan S Gall, Jurgen B Bulitta, Visanu Thamlikitkul, Cornelia B Landersdorfer, Alan Forrest, Roger L Nation, Jian Li, Brian T Tsuji
The objective of this study was to determine the comparative pharmacodynamics of four different carbapenems in combination with polymyxin B (PMB) against carbapenem-resistant Acinetobacter baumannii isolates using time-kill experiments at two different inocula. Two A. baumannii strains (03-149-1 and N16870) with carbapenem minimum inhibitory concentrations (MICs) ranging from 8 to 64 mg/L were investigated in 48-h time-kill experiments using starting inocula of 10(6) CFU/mL and 10(8) CFU/mL. Concentration arrays of ertapenem, doripenem, meropenem and imipenem at 0...
September 20, 2016: International Journal of Antimicrobial Agents
Dimitrios Venetsanos, Sofia Sederholm Lawesson, Eva Swahn, Joakim Alfredsson
AIMS: To provide pharmacodynamic data of crushed and chewed ticagrelor tablets, in comparison with standard integral tablets. METHODS: Ninety nine patients with stable angina were randomly assigned, in a 3:1:1 fashion, to one of the following 180mg ticagrelor loading dose (LD) formulations: A) Integral B) Crushed or C) Chewed tablets. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60min after LD. High residual platelet reactivity (HRPR) was defined as >208 P2Y12 reaction units (PRU)...
October 15, 2016: Thrombosis Research
Sihem Ait-Oudhia, Donald E Mager
Cancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti-cancer compounds is equally challenging, partly based on the complexity of biological and pharmacological systems...
October 22, 2016: Journal of Pharmacokinetics and Pharmacodynamics
Michael L Schulte, Matthew R Hight, Gregory D Ayers, Qi Liu, Yu Shyr, M Kay Washington, H Charles Manning
PURPOSE: This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF (V600E) , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting...
October 21, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Paolo Girardi, Roberto Brugnoli, Giovanni Manfredi, Gabriele Sani
Lithium has been a gold standard in the treatment of bipolar disorder (BD) for several decades. Despite a general reduction in the use of lithium over the past several years, it is effective in the management of both manic and depressive episodes in BD and continues to be recommended as a first-line mood stabilizer. This review provides an overview of the pharmacology of lithium and highlights its clinical profile in the management of BD, focusing on the potential advantages of prolonged-release (PR) versus immediate-release (IR) formulations of lithium...
October 21, 2016: Drugs in R&D
Miriam Krischke, Georg Hempel, Swantje Völler, Nicolas André, Maurizio D'Incalci, Gianni Bisogno, Wolfgang Köpcke, Matthias Borowski, Ralf Herold, Alan V Boddy, Joachim Boos
PURPOSE: Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited. METHODS: We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited...
October 21, 2016: Cancer Chemotherapy and Pharmacology
Dominik Madžar, Anna Geyer, Ruben U Knappe, Stephanie Gollwitzer, Joji B Kuramatsu, Stefan T Gerner, Hajo M Hamer, Hagen B Huttner
BACKGROUND: Clobazam (CLB) is a well characterized antiepileptic drug (AED) that differs from other benzodiazepines by its basic chemical structure and pharmacodynamic properties. Only one previous study examined the efficacy of CLB as add-on therapy in refractory status epilepticus (RSE). METHODS: We analyzed RSE episodes treated in our institution between 2001 and 2012. Successful treatment with CLB was scored if CLB was the last AED added to therapy before RSE termination...
October 21, 2016: BMC Neurology
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