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Clinical Pharmacology and Therapeutics

Mary B Wire, Xiaobin Li, Jianping Zhang, William Sallas, Vassilios Aslanis, Taoufik Ouatas
Our objective was to support initial eltrombopag doses and dose titration based on modeling and simulation of plasma exposure and platelet count response in pediatric patients aged 1-17 years with previously treated chronic immune thrombocytopenia enrolled in 2 clinical studies. Data from 168 pediatric patients were used to develop a life-span population pharmacokinetic and pharmacodynamic model including 3 pharmacokinetic and 4 pharmacodynamic compartments enabling simulation of platelet counts for various starting doses and dose titration schedules...
March 14, 2018: Clinical Pharmacology and Therapeutics
Miriam Saiz-Rodríguez, Daniel Romero-Palacián, Carlos Villalobos-Vilda, José Luis Caniego, Carmen Belmonte, Dora Koller, Eduardo Bárcena, María Talegón, Francisco Abad-Santos
This observational retrospective study assessed antiplatelet response and clinical events after clopidogrel treatment in patients who underwent percutaneous neurointervention, related to CYP2C19 metabolizer status (normal (NM), intermediate/poor (IM-PM) and ultra-rapid (UM); inferred from *2, *3 and *17 allele determination). From 123 patients, IM-PM had higher aggregation value (201.1 vs 137.6 NM, 149.4 UM, p<0.05) and lower response rate (37.5% vs. 69.8% NM, 61.1% UM), along with higher treatment change rate (25% vs...
March 14, 2018: Clinical Pharmacology and Therapeutics
Jason N Moore, Marc R Gastonguay, Chee M Ng, Susan C Adeniyi-Jones, David E Moody, Wenfang B Fang, Michelle E Ehrlich, Walter K Kraft
Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety. The time to NAS stabilization was found to decrease with increasing buprenorphine exposure...
March 8, 2018: Clinical Pharmacology and Therapeutics
John D Davis, Ashish Bansal, David Hassman, Bolanle Akinlade, Meng Li, Zhaoyang Li, Brian Swanson, Jennifer D Hamilton, A Thomas DiCioccio
This open-label drug-drug interaction study assessed whether blockade by dupilumab of interleukin (IL)-4 and IL-13 signaling affects the pharmacokinetics of drugs metabolized by cytochrome P450 (CYP450) enzymes. The pharmacokinetics of five CYP450 substrates given orally (midazolam, omeprazole, S-warfarin, caffeine, and metoprolol, metabolized by CYP3A, CYP2C19, CYP2C9, CYP1A2 and CYP2D6, respectively) were evaluated before and 28 days after initiation of dupilumab treatment (subcutaneous 300 mg weekly) in 14 patients with moderate-to-severe atopic dermatitis...
March 2, 2018: Clinical Pharmacology and Therapeutics
Christof Dücker, Jürgen Brockmöller
No abstract text is available yet for this article.
March 2, 2018: Clinical Pharmacology and Therapeutics
Musaddique Hussain, Chengyun Xu, Mashaal Ahmad, Abdul Majeed, Meiping Lu, Xiling Wu, Lanfang Tang, Ximei Wu
Despite 50 years of extensive research, no definite drug is currently available to treat acute respiratory distress syndrome (ARDS), and the supportive therapies remain the mainstay of treatment. To improve drug development for ARDS, researchers need to deeply analyze the "omics" approaches, reevaluate the suitable therapeutic targets, resolve the problems of inadequate animal modeling, develop the strategies to reduce the heterogeneity, and reconsider new therapeutic and analytical approaches for better designs of clinical trials...
February 27, 2018: Clinical Pharmacology and Therapeutics
Ann E Herman, Leslie W Chinn, Shweta G Kotwal, Elaine R Murray, Rui Zhao, Marilyn Florero, Alyse Lin, Anita Moein, Rena Wang, Meire Bremer, Serika Kokubu, Adrian P Serone, Eva L Hanze, Anders Viberg, Alyssa M Morimoto, Helen R Winter, Tamiko R Katsumoto
GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and non-covalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well-tolerated with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose [SAD] study; ≤250 mg twice daily [BID] and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study)...
February 27, 2018: Clinical Pharmacology and Therapeutics
Robert Palmér, Jukka Mäenpää, Alexandra Jauhiainen, Bengt Larsson, John Mo, Muir Russell, James Root, Susanne Prothon, Ligia Chialda, Pablo Forte, Torbjörn Egelrud, Kristina Stenvall, Philip Gardiner
Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-man study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects...
February 27, 2018: Clinical Pharmacology and Therapeutics
Riccardo Barrile, Andries D van der Meer, Hyoungshin Park, Jacob P Fraser, Damir Simic, Fang Teng, David Conegliano, Justin Nguyen, Abhishek Jain, Mimi Zhou, Katia Karalis, Donald E Ingber, Geraldine A Hamilton, Monicah A Otieno
Clinical development of Hu5c8, a monoclonal antibody against CD40L intended for treatment of autoimmune disorders, was terminated due to unexpected thrombotic complications. These life-threatening side-effects were not discovered during preclinical testing due to the lack of predictive models. In the present study, we describe the development of a microengineered system lined by human endothelium perfused with human whole blood, a 'Vessel-Chip'. The Vessel-Chip allowed us to evaluate key parameters in thrombosis, such as endothelial activation, platelet adhesion, platelet aggregation, fibrin clot formation, and thrombin anti-thrombin (TAT) complexes in the Chip-effluent in response to Hu5c8 in the presence of soluble CD40L...
February 27, 2018: Clinical Pharmacology and Therapeutics
Todd C Skaar, Zeruesenay Desta
This issue of Clinical Pharmacology & Therapeutics (CPT) includes the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for using CYP2D6 genotyping to guide tamoxifen therapy for breast cancer patients. CYP2D6 metabolizes tamoxifen to its more active metabolite, endoxifen, and patients with reduced CYP2D6 activity have reduced circulating endoxifen concentrations. In this associated commentary, we recognize and honor the late Dr. David Flockhart, who began the research and made early fundamental discoveries on tamoxifen that have now resulted in this guideline...
February 23, 2018: Clinical Pharmacology and Therapeutics
Robert N Schuck, Janet Woodcock, Issam Zineh, Peter Stein, Jonathan Jarow, Robert Temple, Thomas Permutt, Lisa LaVange, Julia A Beaver, Rosane Charlab, Gideon M Blumenthal, Sarah E Dorff, Christopher Leptak, Steven Lemery, Hobart Rogers, Badrul Chowdhury, E David Litwack, Michael Pacanowski
Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit-risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment...
February 23, 2018: Clinical Pharmacology and Therapeutics
Aleksi Tornio, Colin N A Palmer, Alex S F Doney
No abstract text is available yet for this article.
February 22, 2018: Clinical Pharmacology and Therapeutics
Claudio Borghi, Maddalena Veronesi
Angiotensin converting enzyme (ACE) inhibitors are extensively used for the prevention and treatment of cardiovascular diseases with a wide range of clinical recommendations. The use of ACE inhibitors can cause the onset of a dry cough, whose prevalence has probably been overestimated because of the lack of adequate control. A correct interpretation of available data requires a careful evaluation of placebo-controlled studies to definitely assess the rate of the most frequent adverse event of ACE inhibition...
February 22, 2018: Clinical Pharmacology and Therapeutics
Sidney H Schnoll
The abuse of opioids in the US is not a new problem. In 1973 David Musto published his book, The American Disease: Origins of Narcotic Control, which described the problem as dating back to the time of the Civil War. Continued attempts to address it through legislation, law enforcement, prevention, treatment, and the development of less abuseable pain relievers have shown limited success.
February 21, 2018: Clinical Pharmacology and Therapeutics
Simona Volpi, Carol Bult, Rex L Chisholm, Patricia A Deverka, Geoffrey S Ginsburg, Howard J Jacob, Melpomeni Kasapi, Howard L McLeod, Dan M Roden, Marc S Williams, Eric D Green, Laura Lyman Rodriguez, Samuel Aronson, Larisa H Cavallari, Joshua C Denny, Lynn Dressler, Julie A Johnson, Teri E Klein, J Steven Leeder, Micheline Piquette-Miller, Minoli Perera, Laura J Rasmussen-Torvik, Heidi L Rehm, Marylyn D Ritchie, Todd C Skaar, Nikhil Wagle, Richard Weinshilboum, Kristin W Weitzel, Robert Wildin, John Wilson, Teri A Manolio, Mary V Relling
Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing...
February 20, 2018: Clinical Pharmacology and Therapeutics
Jesse J Swen, Marga Nijenhuis, Mandy van Rhenen, Nienke J de Boer-Veger, Anne-Marie Buunk, Elisa J F Houwink, Hans Mulder, Gerard A Rongen, Ron H N van Schaik, Jan van der Weide, Bob Wilffert, Vera H M Deneer, Henk-Jan Guchelaar
No abstract text is available yet for this article.
February 20, 2018: Clinical Pharmacology and Therapeutics
Clemens Muehlan, Jules Heuberger, Pierre-Eric Juif, Marie Croft, Joop van Gerven, Jasper Dingemanse
The orexin system regulates sleep and arousal and is targeted by ACT-541468, a new dual orexin receptor antagonist (DORA). Healthy male subjects received a single oral dose of 5-200 mg, to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), mass balance, metabolism, and absolute bioavailability utilizing a14 C-labeled, orally and intravenously (i.v) administered microtracer. The drug was safe and well tolerated; the PK profile was characterized by quick absorption and elimination, with median time to reach maximum concentration (tmax ) of 0...
February 15, 2018: Clinical Pharmacology and Therapeutics
Neeraj Gupta, Michael J Hanley, Paul M Diderichsen, Huyuan Yang, Alice Ke, Zhaoyang Teng, Richard Labotka, Deborah Berg, Chirag Patel, Guohui Liu, Helgi van de Velde, Karthik Venkatakrishnan
No abstract text is available yet for this article.
February 15, 2018: Clinical Pharmacology and Therapeutics
Janice B Schwartz, Raymond L Woosley, Carl C Peck
No abstract text is available yet for this article.
February 13, 2018: Clinical Pharmacology and Therapeutics
Dyfrig A Hughes
Economic evaluations have dispelled a perception that precision medicine, achieved through pharmacogenetic testing, reduces healthcare costs. For many tests aimed at preventing adverse drug reactions, cost-effectiveness analyses predict modest improvements in health benefits and increases in total costs. While there are many uncertainties in estimating the value of testing, factors that influence cost-effectiveness include the rarity of the outcome, the effectiveness of alternative treatments, and the scope and perspective of analysis...
February 13, 2018: Clinical Pharmacology and Therapeutics
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