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Clinical Pharmacology and Therapeutics

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https://www.readbyqxmd.com/read/28516446/a-primary-human-lung-alveolus-on-a-chip-model-of-intravascular-thrombosis-for-assessment-of-therapeutics
#1
Abhishek Jain, Riccardo Barrile, Andries D van der Meer, Akiko Mammoto, Tadanori Mammoto, Karen De Ceunynck, Omozuanvbo Aisiku, Monicah A Otieno, Calvert S Louden, Geraldine A Hamilton, Robert Flaumenhaft, Donald E Ingber
Pulmonary thrombosis is a significant cause of patient mortality, however, there are no effective in vitro models of thrombi formation in human lung microvessels, that could also assess therapeutics and toxicology of antithrombotic drugs. Here we show that a microfluidic lung alveolus-on-a-chip lined by human primary alveolar epithelium interfaced with endothelium, and cultured under flowing whole blood can be used to perform quantitative analysis of organ-level contributions to inflammation-induced thrombosis...
May 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28512771/negative-cardiovascular-consequences-of-small-molecule-immunosuppressants
#2
REVIEW
Harini A Chakkera, Adnan Sharif, Bruce Kaplan
No abstract text is available yet for this article.
May 16, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28512738/first-in-class-composite-angiotensin-receptor-neprilysin-inhibitors-arni-in-practice
#3
REVIEW
Maya H Barghash, Akshay S Desai
No abstract text is available yet for this article.
May 16, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28486791/rare-nox3-variants-confer-susceptibility-to-agranulocytosis-during-thyrostatic-treatment-of-graves-disease
#4
T S Plantinga, P Arts, G H Knarren, A H Mulder, I M Wakelkamp, A R Hermus, L A Joosten, M G Netea, P H Bisschop, W W de Herder, H J Beijers, I J de Bruin, C Gilissen, J A Veltman, A Hoischen, J W Smit, R T Netea-Maier
Agranulocytosis is a rare and serious adverse effect of antithyroid drugs, with unknown etiology. The present study aimed to uncover genetic susceptibility and underlying mechanisms of antithyroid drug-induced agranulocytosis (ATDAC). We studied two independent families with familial Graves' disease, of which several members developed ATDAC. In addition, six sporadic ATDAC patients with Graves' disease were investigated. Whole exome sequencing analysis of affected and unaffected family members was performed to identify genetic susceptibility variants for ATDAC, followed by functional characterization of primary granulocytes from patients and unrelated healthy controls...
May 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28480956/the-renal-effects-of-sglt-2-inhibitors-and-other-anti-diabetic-drugs-clinical-relevance-and-potential-risks
#5
REVIEW
Eirini Lioudaki, Martin Whyte, Emmanouil S Androulakis, Konstantinos G Stylianou, Eugene K Dafnis, Emmanouil S Ganotakis
No abstract text is available yet for this article.
May 8, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28480503/quantitative-evaluations-of-time-course-and-treatment-effects-of-systemic-agents-for-psoriasis-a-model-based-meta-analysis
#6
T Checchio, S Ahadieh, P Gupta, J Mandema, L Puig, R Wolk, H Valdez, H Tan, S Krishnaswami, A Tallman, M Kaur, K Ito
Aggregate data model-based meta-analysis is a regression approach to compare the dose-response and/or time-course across different treatments using summary level data from the literature. Literature search and systematic review following the Cochrane approach yielded 912 sources for investigational and approved treatments for psoriasis. In addition, data for tofacitinib were obtained from an internal database. Tofacitinib is an oral Janus kinase inhibitor. Two mathematical models were developed for Psoriasis Area and Severity Index (PASI) response in moderate to severe psoriasis patients to quantify the time to maximum effect for PASI75 and to evaluate the dose-response relationship for PASI responders (PASI50, PASI75, PASI90, PASI100) at Week 12...
May 8, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28474798/evaluation-of-therapeutics-for-advanced-stage-heart-failure-and-other-severely-debilitating-or-life-threatening-diseases
#7
J S Prescott, P A Andrews, R W Baker, M S Bogdanffy, F O Fields, D A Keller, D M Lapadula, N M Mahoney, D E Paul, S J Platz, D Reese, S A Stoch, J J DeGeorge
Severely debilitating or life-threatening (SDLT) diseases include conditions in which life expectancy is short or quality of life is greatly diminished despite available therapies. As such, the medical context for SDLT diseases is comparable to advanced cancer and the benefit versus risk assessment and development of SDLT disease therapeutics should be similar to that of advanced cancer therapeutics. A streamlined development approach would allow patients with SDLT conditions earlier access to therapeutics and increase the speed of progression through development...
May 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28474735/assessment-of-glomerular-filtration-rate-in-health-and-disease-a-state-of-the-art-review-state-of-the-art-review-for-clinical-pharmacology-and-therapeutics
#8
Andrew S Levey, Lesley A Inker
Acute and chronic kidney diseases affect pharmacokinetics and pharmacodynamics. There has been substantial progress in the past 20 years in the use of GFR estimating equations. In principle, use of a single equation for each filtration marker (creatinine, cystatin C or the combination) for detection, evaluation and management of kidney disease and for drug development and dosing would facilitate clinical practice. We review the principles for assessment of GFR, provide historical perspective and updates regarding use of GFR estimating equations, including assay methods for filtration markers, performance of estimating equations, and recommendations by clinical practice guideline groups and regulatory agencies...
May 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28474732/the-nephrotoxicity-of-vancomycin
#9
REVIEW
Edward J Filippone, Walter K Kraft, John L Farber
No abstract text is available yet for this article.
May 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28466986/targets-for-heart-failure-with-preserved-ejection-fraction
#10
Shane Nanayakkara, David M Kaye
Heart failure (HF) with preserved ejection fraction (HFPEF) is responsible for half of all HF cases, and will be the most common form of HF within the next five years. Previous studies of pharmacological agents in HFPEF have proved neutral or negative, in part due to phenotypic heterogeneity and complex underlying mechanisms. This review summarizes the key molecular and cellular pathways characterized in HFPEF as well as current and future therapies that target these mechanisms. This article is protected by copyright...
May 3, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28455946/response-to-pharmacogenetics-of-voriconazole-cyp2c19-but-also-cyp3a4-need-to-be-genotyped-the-role-of-cyp3a4-and-cyp3a5-polymorphisms-in-clinical-pharmacokinetics-of-voriconazole
#11
T J Walsh, B Moriyama, S R Penzak, T E Klein, K E Caudle
No abstract text is available yet for this article.
April 29, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28445610/population-pharmacokinetics-of-liposomal-irinotecan-in-patients-with-cancer
#12
Bambang Adiwijaya, Jaeyeon Kim, Istvan Lang, Tibor Csõszi, Antonio Cubillo, Jen-Shi Chen, Mark Wong, Joon Oh Park, Jun Suk Kim, Kun Ming Rau, Bohuslav Melichar, Javier Gallego, Jonathan Fitzgerald, Bruce Belanger, Istvan Molnar, Wen Wee Ma
nal-IRI is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with non-liposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from 6 studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase 3 study in pancreatic cancer NAPOLI1...
April 26, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28444890/utilizing-pbpk-modeling-to-evaluate-the-potential-of-a-significant-drug-drug-interaction-between-clopidogrel-and-dasabuvir-a-scientific-perspective
#13
V Arya, P Zhao, K S Reynolds, P Mishra, I R Younis
Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-β-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK...
April 26, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28437851/fexofenadine-a-putative-in-vivo-p-glycoprotein-probe-fails-to-predict-clearance-of-the-substrate-tacrolimus-in-renal-recipients
#14
Thomas Vanhove, Thomas Bouillon, Henriëtte de Loor, Pieter Annaert, Dirk R J Kuypers
Whether combined use of probe drugs for CYP3A4 and P-glycoprotein can clarify the relative contribution of these proteins to pharmacokinetic variability of a dual substrate like tacrolimus has never been assessed. Seventy renal recipients underwent simultaneous 8-hour pharmacokinetic profiles for tacrolimus, the CYP3A4 probe midazolam and the putative P-glycoprotein probe fexofenadine. Patients were genotyped for polymorphisms in CYP3A5, CYP3A4, ABCB1, ABCC2 and SLCO2B1, -1B1 and 1B3. Carriers of the ABCB1 2677G>A polymorphism displayed lower fexofenadine Cmax (-66%; P=0...
April 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28437834/elucidation-of-factor-viii-activity-pharmacokinetics-a-pooled-population-analysis-in-hemophilia-a-patients-treated-with-moroctocog-alfa
#15
João A Abrantes, Elisabet I Nielsen, Joan Korth-Bradley, Lutz Harnisch, Siv Jönsson
This study investigated the disposition of coagulation factor VIII activity in 754 moderate to severe hemophilia A patients following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race and analytical assay were identified as significant predictors of factor VIII disposition...
April 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28419467/refining-liver-safety-risk-assessment-application-of-mechanistic-modeling-and-serum-biomarkers-to-cimaglermin-alfa-ggf2-clinical-trials
#16
Diane M Longo, Grant T Generaux, Brett A Howell, Scott Q Siler, Daniel J Antoine, Donald Button, Anthony Caggiano, Andrew Eisen, Jennifer Iaci, Ric Stanulis, Tom Parry, Merrie Mosedale, Paul B Watkins
Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase 1 trials were suspended when 2 cimaglermin alfa-treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin meeting current FDA criteria for a serious liver safety signal (i.e. "Hy's Law"). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death...
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28419437/a-new-paradigm-learn-learn-more-dose-exposure-response-at-the-centre-of-drug-development-and-regulatory-approval
#17
REVIEW
Alan Maloney
No abstract text is available yet for this article.
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28419431/moving-beyond-maximum-tolerated-dose-for-targeted-oncology-drugs-use-of-clinical-utility-index-to-optimize-venetoclax-dosage-in-multiple-myeloma-patients
#18
Kevin J Freise, Aksana K Jones, Maria E Verdugo, Rajeev M Menon, Paulo C Maciag, Ahmed Hamed Salem
Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a Phase 1b venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify sub-populations with different responses and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment...
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28411400/physiologically-based-pharmacokinetic-modeling-suggests-limited-drug-drug-interaction-between-clopidogrel-and-dasabuvir
#19
Mohamad Shebley, Wentao Fu, Prajakta Badri, Daniel A J Bow, Volker Fischer
Dasabuvir, a non-nucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically-based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data...
April 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28398598/pharmacogenomics-based-point-of-care-clinical-decision-support-significantly-alters-drug-prescribing
#20
Peter H O'Donnell, Nisha Wadhwa, Keith Danahey, Brittany A Borden, Sang Mee Lee, Julianne P Hall, Catherine Klammer, Sheena Hussain, Mark Siegler, Matthew J Sorrentino, Andrew M Davis, Yasmin A Sacro, Rita Nanda, Tamar S Polonsky, Jay L Koyner, Deborah L Burnet, Kristen Lipstreuer, David T Rubin, Cathleen Mulcahy, Mary E Strek, William Harper, Adam S Cifu, Blase Polite, Linda Patrick-Miller, Kiang-Teck J Yeo, Edward K Y Leung, Samuel L Volchenboum, Russ B Altman, Olufunmilayo I Olopade, Walter M Stadler, David O Meltzer, Mark J Ratain
Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green/genomically favorable, yellow/genomic caution, red/high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint...
April 11, 2017: Clinical Pharmacology and Therapeutics
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