Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment. Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.
Sleep-disordered breathing, and particularly the highly prevalent obstructive sleep apnea syndrome, is a multicomponent disorder combining intermittent hypoxia (IH), sleep fragmentation, and obstructed respiratory efforts. It is frequently associated with comorbidities and leads to numerous complications, including cardiovascular consequences that are conditioned by genetic predisposition and environment. The complexity of the disease and the reduced possibilities for patient investigations, especially at the tissue level, have limited progress in the understanding of sleep apnea pathophysiology and in the development of specific treatments. Animal models make it possible to study the causative mechanisms (essentially upper airway dysfunction) and the consequences (cardiovascular, metabolic, and neurological alterations) of nocturnal respiratory events without the confounding factors that occur in humans. Such studies have revealed some of the pathophysiological mechanisms and enabled the recognition of IH as the most important sleep apnea component underlying cardiovascular complications. We review different animal models used to assess detrimental sleep apnea-related cardiovascular consequences: blood pressure elevation, impaired vasoreactivity, structural arterial remodeling leading to atherosclerosis, cardiac remodeling, and myocardial infarction. We also review experimental evidence of beneficial effects of IH. By combining clinical and experimental research, these models will contribute to the understanding of differential patient susceptibility and to the elaboration of prevention strategies and tailored treatments for sleep apnea patients.
Ribavirin in combination with alpha 2 interferon is the consensus treatment for chronic hepatitis C. However, recent preliminary pharmacological studies have suggested that the bioavailability of ribavirin displays great interindividual variability. In order to monitor serum ribavirin levels during combination treatment, we developed and validated a quantitative assay using an approach adaptable for routine hospital laboratories. The method involved solid-phase extraction on phenyl boronic acid cartridges followed by high-performance liquid chromatography with a C 18 -bonded silica column and a mobile phase containing 10 mM ammonium phosphate buffer (with the pH adjusted to 2.5) and UV detection (207 nm). The sensitivity, recovery, linearity of the calibration curve, intra-and interassay accuracies, precision, and stability at 4°C were consistent with its use in the laboratory routine. In addition, other nucleoside analogues sometimes used with ribavirin in patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus did not interfere with the quantification of ribavirin levels. The ribavirin concentration was quantified in 24 serum samples from patients with chronic hepatitis C treated with a combination of ribavirin and alpha 2 interferon. The mean serum ribavirin concentration was 2.67 ؎ 1.06 g/ml (n ؍ 24) at week 12 of treatment (W12) and 3.24 ؎ 1.35 g/ml (n ؍ 24) at week 24 of treatment (W24). In addition, ribavirin concentrations displayed high interindividual variabilities: the coefficients of variation of the serum ribavirin concentrations adjusted to the administered dose were 44 and 48% at W12 and W24, respectively. Moreover, the ribavirin concentration was higher in patients with a sustained virological response (n ؍ 11) than in patients with treatment failure (n ؍ 13), with significant intergroup differences at W12 (P ؍ 0.030) and W24 (P ؍ 0.049). The present study describes a simple analytical method for the quantification of ribavirin in human serum that could be a useful tool for the monitoring of ribavirin concentrations in HCV-infected patients in order to improve the efficacy and safety of therapy with ribavirin plus interferon.
Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid, the quantification of which provides a novel approach to the assessment of oxidative stress in vivo. The main objective of this study was to quantify the urinary levels of isoprostaglandin F(2alpha) type III (iPF(2alpha)-III), an F(2)-isoprostane, in patients with pulmonary hypertension (PHT) in comparison with healthy controls. The secondary objective was to test whether baseline iPF(2alpha)-III levels correlate to the reversibility of pulmonary hypertension in response to inhaled NO challenge. Urinary iPF(2alpha)-III levels were measured by gas chromatography-mass spectrometry in 25 patients with PHT, 14 of whom were investigated for response to inhaled NO challenge. Urinary iPF(2alpha)-III levels in PHT patients (225 +/- 27 pmol/mmol creatinine) were 2.3 times as high as in controls (97 +/- 7 pmol/mmol creatinine, p < 0.001). The mean pulmonary arterial pressure variation and the pulmonary vascular resistance variation in response to inhaled NO were correlated to basal iPF(2alpha)-III levels. This study shows that oxidative stress is increased in patients with pulmonary hypertension. Furthermore, iPF(2alpha)-III levels inversely correlate to pulmonary vasoreactivity. These observations are consistent with the hypothesis that free radical generation is involved in PHT pathogenesis.
f Voriconazole (VRC) plasma trough concentrations (C min ) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra-and interindividual variation of VRC C min throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC C min (n ؍ 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRC C min inter-and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC C min (r ؍ 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC C min . Considering oral therapy, patients with a genetic score of <2 had higher initial VRC C min /D than patients with a genetic score of >2 (P ؍ 0.009). Subsequent VRC C min remained influenced by the genetic score (P ؍ 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC C min in AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC C min within the therapeutic range.
Coronary heart disease is frequently associated with obstructive sleep apnea syndrome and treating obstructive sleep apnea appears to significantly improve the outcome in coronary heart disease. Thus we have developed a rat model of chronic intermittent hypoxia (IH) to study the influence of this condition on myocardial ischemia-reperfusion tolerance and on functional vascular reactivity. Wistar male rats were divided in three experimental groups (n = 12 each) subjected to chronic IH (IH group), normoxia (N group), or control conditions (control group). IH consisted of repetitive cycles of 1 min (40 s with inspired O(2) fraction 5% followed by 20 s normoxia) and was applied for 8 h during daytime, for 35 days. Normoxic cycles were applied in the same conditions, inspired O(2) fraction remaining constant at 21%. On day 36, mean arterial blood pressure (MABP) was measured before isolated hearts were submitted to an ischemia-reperfusion protocol. The thoracic aorta and left carotid artery were also excised for functional reactivity studies. MABP was not significantly different between the three experimental groups. Infarct sizes (in percent of ventricles) were significantly higher in IH group (46.9 +/- 3.6%) compared with N (26.1 +/- 2.8%) and control (21.7 +/- 2.1%) groups. Vascular smooth muscle function was similar in aorta and carotid arteries from all groups. The endothelium-dependent relaxation in response to acetylcholine was also similar in aorta and carotid arteries from all groups. Chronic IH increased heart sensitivity to infarction, independently of a significant increase in MABP, and did not affect vascular reactivity of aorta and carotid arteries.
Isoprostanes are a family of compounds produced from polyunsaturated fatty acids via a free-radical-catalysed mechanism. F2-isoprostanes are prostaglandin F2α isomers derived from arachidonic acid. These compounds induce potent vasoconstriction, mediated primarily by TP receptor stimulation, and in some vessels by the release of cyclooxygenase products. This vasoconstriction may be modulated by the endothelium through the release of NO. Potent vasoconstriction is also observed with E2-isoprostanes. Experimental and clinical data suggest a role for F2-isoprostanes in atherogenesis. These compounds can be detected in free forms in biological fluids as well as esterified in low-density lipoproteins or cell membranes. Their quantification represents a reliable marker of lipid peroxidation. Elevated levels of F2-isoprostanes in biological fluids in pathological conditions including atherosclerosis, ischaemia-reperfusion injury, and inflammatory vascular diseases, suggest a relationship between lipid peroxidation and such diseases. F2-isoprostanes are currently being investigated as non-invasive quantitative markers to monitor the response to anti-oxidant treatment.
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