Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data

Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment.

Download Full-text

The impact of change in serum C-reactive protein level on the prediction of effects of molecular targeted therapy in patients with metastatic renal cell carcinoma

BJU International ◽

10.1111/bju.13260 ◽

2015 ◽

Vol 117 (6B) ◽

pp. E67-E74 ◽

Cited By ~ 17

Author(s):

Jun Teishima ◽

Kohei Kobatake ◽

Hiroyuki Kitano ◽

Hirotaka Nagamatsu ◽

Kousuke Sadahide ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Protein Level ◽

Renal Cell ◽

Molecular Targeted Therapy ◽

C Reactive Protein ◽

Reactive Protein ◽

The Impact

Download Full-text

Impact of Genetic and Environmental Factors on hsCRP Concentrations and Response to Therapeutic Agents

Clinical Chemistry ◽

10.1373/clinchem.2008.117754 ◽

2009 ◽

Vol 55 (2) ◽

pp. 256-264 ◽

Cited By ~ 33

Author(s):

Jian Shen ◽

Jose M Ordovas

Keyword(s):

Environmental Factors ◽

Genetic Polymorphisms ◽

Genetic Variants ◽

Inflammatory Marker ◽

Lipid Lowering ◽

C Reactive Protein ◽

Reactive Protein ◽

Fenofibrate Treatment ◽

Genetic And Environmental Factors ◽

The Impact

Abstract Background: Inflammation plays an instrumental role in all stages of atherosclerosis. High-sensitivity C-reactive protein (hsCRP), a systemic inflammatory marker, has been gaining recognition as an independent risk factor for cardiovascular disease (CVD). Both baseline hsCRP concentrations and drug-induced hsCRP changes are highly variable and potentially subject to genetic regulation. Content: This review summarizes the current studies examining the effect of genetic and environmental factors on baseline plasma hsCRP concentrations, with a main focus on C-reactive protein, pentraxin-related (CRP) genetic polymorphisms and various dietary components that affect hsCRP concentrations. We also address the association of CRP genetic variations with CVD risk, a relationship that may support or refute the causality of CRP in the atherosclerotic process. Moreover, we discuss the impact of CRP genetic polymorphisms on hsCRP changes in response to 3-week fenofibrate treatment in the genetic intervention of the Genetics of Lipid Lowering Drugs and Diet Network study. Summary: Genetic variants on the CRP locus and other loci and dietary and lifestyle factors are responsible for the interindividual variability of plasma hsCRP concentrations. CRP genetic variants further influence differing plasma hsCRP response after 3-week fenofibrate treatment in patients with metabolic syndrome. Future studies focusing on the influence and interaction of genetic variation on the hsCRP response to dietary and other behavior modification as well as drug treatment could have important implications for the development of more personalized preventive and therapeutic approaches to reduce CVD.

Download Full-text

Ventilator-Associated Tracheobronchitis Increases the Length of Intensive Care Unit Stay

Infection Control and Hospital Epidemiology ◽

10.1086/671274 ◽

2013 ◽

Vol 34 (8) ◽

pp. 800-808 ◽

Cited By ~ 19

Author(s):

Marios Karvouniaris ◽

Demosthenes Makris ◽

Efstratios Manoulakas ◽

Paris Zygoulis ◽

Konstantinos Mantzarlis ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Protein Level ◽

Significant Risk ◽

University Hospital ◽

C Reactive Protein ◽

Prolonged Stay ◽

Reactive Protein ◽

Icu Stay ◽

The Impact

Objective.To investigate prospectively the clinical course and risk factors for ventilator-associated tracheobronchitis (VAT) and the impact of VAT on intensive care unit (ICU) morbidity and mortality.Design.Prospective cohort study.Setting.University Hospital Larissa, Larissa, GreecePatients.Critical care patients who received mechanical ventilation for more than 48 hours were prospectively studied between 2009 and 2011.Methods.The modified Clinical Pulmonary Infection Score, white blood cell count, and C-reactive protein level were systematically assessed every 2 days for the first 2 weeks of ICU stay. Bronchial secretions were assessed daily. Quantitative cultures of endotracheal secretions were performed on the first ICU day for every patient and every 2 days thereafter for the first 2 weeks or more at the discretion of the attending physicians. Definition of VAT was based on previously published criteria.Results.A total of 236 patients were observed; 42 patients (18%) presented with VAT. Gram-negative pathogens, which were usually multidrug resistant, were responsible for 92.9% of cases. Patients with a neurosurgical admission presented with VAT significantly more often than did other ICU patients (28.5% vs 14.1%; P = .02). The occurrence of VAT was a significant risk factor for increased duration of ICU stay (OR [95% CI], 3.04 [1.35-6.85]; P = .01). Age (OR [95% CI], 1.04 [1.015-1.06]; P = .02), Acute Physiology and Chronic Health Evaluation II score (OR [95% CI], 1.08 [1.015-1.16]; P = .02), and C-reactive protein level at admission (OR [95% CI], 1.05 [1.011.1]; P = .02) were independent factors for ICU mortality.Conclusions.VAT is a nosocomial infection that might be associated with prolonged stay in the ICU, especially in neurocritical patients. VAT was not associated with increased mortality in our study.

Download Full-text