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Clinical Pharmacology and Therapeutics

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https://www.readbyqxmd.com/read/28925027/a-prospective-international-study-on-adherence-to-treatment-in-305-patients-with-flaring-sle-assessment-by-drug-levels-and-by-self-administered-questionnaires
#1
Nathalie Costedoat-Chalumeau, Frédéric Houssiau, Peter Izmirly, Véronique Le Guern, Sandra Navarra, Meenakshi Jolly, Guillermo Ruiz-Irastorza, Gabriel Baron, Eric Hachulla, Nancy Agmon-Levin, Yehuda Shoenfeld, Francesca Dall'Ara, Jill Buyon, Christophe Deligny, Ricard Cervera, Estibaliz Lazaro, Holy Bezanahary, Gaëlle Leroux, Nathalie Morel, Jean-François Viallard, Christian Pineau, Lionel Galicier, Ronald Van Vollenhoven, Angela Tincani, Hanh Nguyen, Guillaume Gondran, Noel Zahr, Jacques Pouchot, Jean-Charles Piette, Michelle Petri, David Isenberg
Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by HPLC. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ<200ng/ml or undetectable desethylchloroquine), and self-administered questionnaires (MASRI<80% or MMAS-8<6). Drug levels defined 18.4% of the patients as severely nonadherent. In multivariate analyses, younger age, non-use of steroids, higher BMI and unemployment were associated with nonadherence by drug level...
September 19, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28913918/clopidogrel-in-critically-ill-patients
#2
Christian Schoergenhofer, Eva-Luise Hobl, Peter Schellongowski, Gottfried Heinz, Walter Speidl, Jolanta Siller-Matula, Monika Schmid, Raute Sunder-Plaßmann, Thomas Stimpfl, Matthias Hackl, Bernd Jilma
Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the CYP450 activated pro-drug clopidogrel (n=43) and the half-life of the similarly metabolized pantoprazole (n=16) in critically ill patients. ADP-induced aggregometry in whole blood classified 74% (95% confidence intervals 59-87%) of critically ill patients as poor responders (n=43), and 65% (49-79%) responded poorly according to the VASP-P assay...
September 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28913853/dose-rationalisation-of-pembrolizumab-and-nivolumab-using-pharmacokinetic-modelling-and-simulation-and-cost-analysis
#3
Kayode Ogungbenro, Alkesh Patel, Robert Duncombe, Richard Nuttall, James Clark, Paul Lorigan
Pembrolizumab and nivolumab are highly selective anti PD-1 antibodies approved for the treatment of advanced malignancies. Variable exposure and significant wastage have been associated with body size dosing of monoclonal antibodies. The following dosing strategies were evaluated using simulations: body weight, dose banding, fixed dose and pharmacokinetics based method. The relative cost to body weight dosing for band, fixed 150 mg and 200 mg, and pharmacokinetics derived strategies were -15%, -25%, +7% and -16% for pembrolizumab and -8%, -6%, and -10% for band, fixed, and pharmacokinetics derived strategies for nivolumab...
September 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28913827/when-more-is-less-an-exploratory-study-of-the-precautionary-reporting-bias-and-its-impact-on-safety-signal-detection
#4
Kevin Klein, Joep Hg Scholl, Marie L De Bruin, Eugène P van Puijenbroek, Hubert Gm Leufkens, Pieter Stolk
Concerns have been expressed that large numbers of non-value added reports have been accumulating in ADR databases, for example via patient support programs. We performed an assessment of the impact of such reports, to which we refer to as 'precautionary reports', on safety signal detection in the Netherlands. The case narratives of ADR reports of three case products were screened with text-mining algorithms to identify those reports that lack a causal relationship with the suspected medicinal product. We demonstrate that precautionary reports impede the optimal use of the pharmacovigilance system by, on the one hand, masking safety signals and, on the other hand, creating spurious signals...
September 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28913826/modeling-tolerance-development-for-the-effect-on-heart-rate-of-the-selective-s1p1-receptor-modulator-ponesimod
#5
Dominik Lott, Thorsten Lehr, Jasper Dingemanse, Andreas Krause
Ponesimod is a selective sphingosine-1-phosphate-1 (S1P1 ) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. This effect disappears with repeated dosing, enabling development of innovative up-titration regimens to optimize patient safety. There are currently no published pharmacokinetic/pharmacodynamic models describing the heart rate reduction of S1P receptor modulators in humans. The model developed here provides quantification of this effect for ponesimod...
September 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28905988/lack-of-bioequivalence-among-low-dose-enteric-coated-aspirin-preparations
#6
Dermot Cox, Desmond Fitzgerald
Low-dose aspirin (75 mg or 81 mg) is considered to be the lowest effective dose for cardiovascular protection, however, the use of enteric preparations has created a source of variability in bioavailability. As part of regulatory requirements we carried out bioequivalence tests for two 75 mg enteric-coated aspirin preparations (Caprin and Protek) using Nu-Seals 75 mg aspirin as the comparator. The primary endpoint was serum thromboxane levels after 14 days of treatment. Protek failed to meet bioequivalence, as it was significantly less effective than Nu-Seals...
September 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28901535/a-benefit-risk-analysis-approach-to-capture-regulatory-decision-making-multiple-myeloma
#7
G K Raju, Karthik Gurumurthi, Reuben Domike, Dickran Kazandjian, Ola Landgren, Gideon M Blumenthal, Ann Farrell, Richard Pazdur, Janet Woodcock
Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS) due to an increased focus on quality of life instead of quantity of life...
September 13, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28891208/serum-microrna-150-predicts-prognosis-for-early-stage-non-small-cell-lung-cancer-and-promotes-tumor-cell-proliferation-by-targeting-tumor-suppressor-gene-srcin1
#8
Liren Zhang, Jing Lin, Yuanqing Ye, Taro Oba, Emanuela Gentile, Jie Lian, Jing Wang, Yang Zhao, Jian Gu, Ignacio I Wistuba, Jack A Roth, Lin Ji, Xifeng Wu
This integrative multistage study was aimed to identify circulating miRNAs as prognostic biomarkers and investigate treatment target for early-stage non-small cell lung cancer (NSCLC) patients. In stage I-II NSCLC patients, we screened and validated miRNA ratio signatures predictive of prognosis in serum. In tumor, we found that the expression of miR-150 in identified miRNA signatures was also associated with survival. Increased miR-150 expression promoted NSCLC cell proliferation and migration and vice versa...
September 10, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28891044/considerations-for-evaluating-treatment-effects-from-randomized-clinical-trials
#9
Stephen J Ruberg, Mouna Akacha
This paper focuses on the choice of treatment effect measures in randomized clinical trials (RCT). Traditionally, an intention-to-treat (ITT) analysis is conducted with an implicit understanding that a treatment-policy effect is of greatest interest. In this paper we contend that this approach may not always provide accurate information about clinically meaningful treatment effects, and we present an argument that for any RCT it is desirable to require an explicit definition of what treatment effect is of primary interest, known as the 'estimand'...
September 10, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28877336/identification-of-%C3%AF-or-%C3%AF-1-hydroxylated-medium-chain-acylcarnitines-as-novel-urinary-biomarkers-for-cyp3a-activity
#10
Bora Kim, Jieon Lee, Kwang-Hee Shin, SeungHwan Lee, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho
Quantitative models of endogenous metabolites are useful in predicting CYP3A-mediated drug-drug interactions. This study aimed to identify novel predictive markers for the magnitude of CYP3A induction and inhibition in male and female subjects using an untargeted metabolomics approach. Here, we report five ω- or (ω-1)-hydroxylated medium-chain acylcarnitines as novel CYP3A4 markers. As CYP4 catalyzes the ω- or (ω-1)-hydroxylation of various medium-chain fatty acids (MCFAs), recombinant enzyme assays were used to determine the ω- and (ω-1)-hydroxylation activities of CYP3A4, CYP4A11, and CYP4F2...
September 6, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28875569/group-based-trajectory-models-assessing-adherence-to-antihypertensive-medication-in-older-adults-in-a-community-pharmacy-setting
#11
Paul Dillon, Derek Stewart, Susan M Smith, Paul Gallagher, Gráinne Cousins
Antihypertensive medication non-adherence is highly prevalent, leading to uncontrolled blood pressure. Methods that facilitate the targeting and tailoring of adherence interventions in clinical settings are required. Group-based trajectory modelling (GBTM) is a newer method to evaluate adherence using pharmacy dispensing (refill) data that has advantages over traditional refill adherence metrics (e.g. Proportion of Days Covered) by identifying groups of patients who may benefit from adherence interventions, and identifying patterns of adherence behaviour over time which may facilitate tailoring of an adherence intervention...
September 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28875506/medications-recommended-for-secondary-prevention-after-first-acute-coronary-syndrome-effectiveness-of-treatment-combinations-in-real-life-setting
#12
Julien Bezin, Olaf H Klungel, Régis Lassalle, Caroline Dureau-Pournin, Nicholas Moore, Antoine Pariente
Long-term effectiveness of Evidence-Based Cardiovascular Medications (EBCMs) indicated after Acute Coronary Syndrome (ACS) needs to be assessed considering the combination effects for these drugs recommended in association. Using a nationwide database, we conducted a cohort study to evaluate the effectiveness of all possible incomplete EBCMs-based combinations as compared to that associating the four recommended EBCMs over up to five years of follow-up. Among the 31,668 patients included, 22.9% had ACS recurrence or died during follow-up...
September 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28875498/comparative-study-of-effects-of-vonoprazan-and-esomeprazole-on-anti-platelet-function-of-clopidogrel-or-prasugrel-in-relation-to-cyp2c19-genotype
#13
Takuma Kagami, Mihoko Yamade, Takahiro Suzuki, Takahiro Uotani, Yasushi Hamaya, Moriya Iwaizumi, Satoshi Osawa, Ken Sugimoto, Kazuo Umemura, Hiroaki Miyajima, Takahisa Furuta
Drug-drug interaction between anti-acid and anti-platelet agents has not been fully elucidated. Vonoprazan, a new potassium competitive acid blocker, has been available in Japan. CYP2C19 and CYP3A4 are involved in the metabolism of clopidogrel, prasugrel, esomeprazole and vonoprazan. Using P2Y12 assay, we compared the effects of vonoprazan and esomeprazole on the anti-platelet functions of clopidogrel or prasugrel in 31 healthy Japanese volunteers [14 CYP2C19 homo-extensive (homo-EMs), 9 hetero-extensive (hetero-EMs), and 8 poor metabolizers (PMs)]...
September 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28865143/identifying-patients-with-high-data-completeness-to-improve-validity-of-comparative-effectiveness-research-in-electronic-health-records-data
#14
Kueiyu Joshua Lin, Daniel E Singer, Robert J Glynn, Shawn N Murphy, Joyce Lii, Sebastian Schneeweiss
Electronic health records (EHR)-discontinuity, i.e., having medical information recorded outside of the study EHR system, is associated with substantial information bias in EHR-based comparative effectiveness research (CER). We aimed to develop and validate a prediction model identifying patients with high EHR-continuity to reduce this bias. Based on 183,739 patients aged ≥65 in EHRs from two US provider networks linked with Medicare claims data from 2007-2014, we quantified EHR-continuity by Mean Proportion of Encounters Captured (MPEC) by the EHR system...
September 2, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28857147/safety-and-ergogenic-properties-of-combined-aminophylline-and-ambrisentan-in-hypoxia
#15
Thies Schroeder, Claude A Piantadosi, Michael J Natoli, Julie Autmizguine, Michael Cohen-Wolkowieczs, Karyn L Hamilton, Christopher Bell, Jelena Klawitter, Uwe Christians, David C Irwin, Robert J Noveck
We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500mg) plus ambrisentan (5mg) in normoxic volunteers. Subsequently, a placebo-controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267m)...
August 31, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28850705/possible-strategies-to-make-warfarin-dosing-algorithm-prediction-more-accurately-in-patients-with-extreme-dose
#16
LETTER
Han Yan, Ji-Ye Yin, Wei Zhang, Xi Li
No abstract text is available yet for this article.
August 29, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28850676/addressing-pharmaceutical-injuries-the-u-s-landscape
#17
Cecilia Bakker, Nicholaas Honig
The legal landscape for addressing an injury related to the use of a pharmaceutical product varies from country to country. Approximately 10 countries have adopted some form of no-fault compensation, in which an individual must establish that they sustained an injury caused by the medicine, but need not demonstrate that the manufacturer acted negligently in order to recover. This commentary compares and contrasts the approach taken in Japan with that in the United States.
August 29, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28836272/psychedelic-drugs-as-therapeutics-no-illusions-about-the-challenges
#18
Edward M Sellers, Deborah B Leiderman
Interest in the potential therapeutic benefits of psychedelic agents has recently increased. In addition to psilocybin, a wide variety of agents with psychedelic properties have been proposed and partially tested. However, the challenges of obtaining approval to market a restricted psychotomimetic agent are formidable.
August 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28836267/when-and-how-can-real-world-data-analyses-substitute-for-randomized-controlled-trials
#19
Jessica M Franklin, Sebastian Schneeweiss
Regulators consider randomized controlled trials (RCTs) as the gold standard for evaluating the safety and effectiveness of medications, but their costs, duration, and limited generalizability have caused some to look for alternatives. Real world evidence based on data collected outside of RCTs, such as registries and longitudinal healthcare databases, can sometimes substitute for RCTs, but concerns about validity have limited their impact. Greater reliance on such real world data (RWD) in regulatory decision-making requires understanding why some studies fail while others succeed in producing results similar to RCTs...
August 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28836264/development-of-molecularly-targeted-therapies-to-treat-pediatric-malignancies
#20
Clinton F Stewart, Giles W Robinson
Drugs and biologics developed to treat children with cancer have been historically developed in adults for adult indications. Although leading to many useful drugs and biologics to treat pediatric cancer, future development of molecularly targeted therapies (MTTs) should be directed toward pediatric tumors more specifically to maximize antitumor efficacy while minimizing acute morbidity and long-term disability. This will put pediatric clinicians closer to the goal of cure for all children diagnosed with cancer...
August 24, 2017: Clinical Pharmacology and Therapeutics
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