Elodie Gautier-Veyret

Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis

Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E-/- mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p<0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.

Leukotrienes as a molecular link between obstructive sleep apnoea and atherosclerosis

Leukotrienes are biologically active lipid mediators of inflammation involved in atherogenesis. Obstructive sleep apnoea (OSA) patients exhibit early atherosclerosis and activation of the leukotriene pathway. In OSA patients, the production of leukotrienes is increased in relation to OSA severity and in vitro exposure of immune cells to intermittent hypoxia increases leukotriene pathway transcription. Moreover, the leukotriene transcriptional pathway is associated with early vascular remodelling. Lastly, obesity is a major confounding factor for leukotriene activation in OSA. The aim of this review was to focus on the intricate network of leukotrienes, chronic intermittent hypoxia, and atherosclerosis, with an emphasis on the role of leukotrienes in the early atherosclerosis observed in OSA patients.

Pharmacogenetics may influence the impact of inflammation on voriconazole trough concentrations

How pharmacogenetics modulates the inhibitory effects of inflammation on voriconazole trough concentration (Cmin) remains unknown. In 29 recipients of allogeneic hematopoietic stem cell transplantation retrospectively studied, both a genetic score (which aggregated CYP2C19 and CYP3A genotypes) and inflammation significantly influenced voriconazole Cmin (n = 260). A trend toward (p = 0.03) a greater impact of inflammation in patients with the highest genetic score (corresponding to ultra-rapid metabolizers) was observed. Further researches are needed to confirm these data.

Which place of pharmacological approaches beyond continuous positive airway pressure to treat vascular disease related to obstructive sleep apnea

ABSTRACT Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete upper airway obstruction, occurring during sleep, leading to chronic intermittent hypoxia (IH), which harms the cardiovascular system. OSA is associated with both functional and structural vascular alterations that contribute to an increased prevalence of fatal and non‐fatal cardiovascular events. OSA is a heterogeneous disease with respect to the severity of hypoxia, the presence of daytime symptoms, obesity, and cardiovascular comorbidities. Various clusters of OSA phenotypes have been described leading to more highly personalized treatment. The aim of this review is to describe the various therapeutic strategies including continuous positive airway pressure (CPAP), oral appliances, surgery, weight loss, and especially pharmacological interventions that have been evaluated to reduce vascular alterations in both OSA patients and preclinical animal models. Conventional therapies, predominantly CPAP, have a limited impact on vascular alterations in the presence of co‐morbidities. A better knowledge of pharmacological therapies targeting IH‐induced vascular alterations will facilitate the use of combined therapies and is crucial for designing clinical trials in well‐defined OSA phenotypes.

A genetic score combining CYP450 2C19 and 3A4 genotypes to predict voriconazole plasma exposure

We readwith great interest the recent publication entitled ‘Impact of CYP2C19 genetic polymorphisms on voriconazole dosing and exposure in adult patients with invasive fungal infections’ by Lamoureux et al [1] recently published in International Journal of Antimicrobial Agents. This article confirms that the CYP2C19 genotype has a significant influence on plasma exposure of voriconazole (VRC). The authors concluded that dose adjustment based on early CYP2C19 genotyping, together with therapeutic drugmonitoring (TDM), may improve clinical outcomes and may help determine the cause of the frequently observed subtherapeutic concentrations of VRC. However, and as mentioned by the authors, VCR undergoes several CYP-dependent metabolic pathways: the 2C19 pathway that has been extensively studied, but also the CYP3A4/5 pathway that has received less attention (see Fig. 1). A new CYP3A4 single nucleotide polymorphism (SNP) (CYP3A4*22;rs35599367) associated with low hepatic CYP3A4 expression and activity has been identified in the last few years as a promising CYP3A4 allele for personalizing pharmacotherapy [2]. This SNP, the frequency of which varies from 6% to 13% in populations with European ancestry, was already identified as a determinant of several drug metabolisms [3]. We recently clearly demonstrated in recipients of allogeneic haematopoietic stem cell transplantation the impact of this SNP on VRC concentrations, since the presence of one *22 allele was associated with increased initial VRC trough concentrations, an effect independent of the CYP2C19 genotype [4]. Unfortunately, this study was not mentioned in the paper by Lamoureux et al [1], albeit it was the first to provide strong evidence for the impact of CYP3A4*22 on VRC exposure. In addition, another SNP (rs4646437) located in an intronic area of CYP3A4 and associated with higher VRC levels was also described in a Chinese cohort [5]. In this work, the influence of CYP3A4*22 could not be investigated since the allelic frequency of this polymorphism is null in the East Asian population [5]. These findings support that in addition to CYP2C19, the CYP3A4 genotype probably also plays a major role in VRC metabolism. Thus, and as we recently proposed [4], an early dose adjustment of VRC based not only on CYP2C19 genotype but on a combined genetic score that includes the genotypes of both CYP2C19 and

Contribution of a Simple Bioassay in Effective Therapeutic Drug Monitoring of Posaconazole and Voriconazole.

Background: With the constantly growing incidence of invasive fungal infections, any failure of antifungal treatment is worrying. Azole antifungals present high variability of their plasma trough concentrations (Cmin), justifying their therapeutic drug monitoring (TDM). The authors aimed to develop a simple bioassay to determine the in vitro growth inhibition diameter (ID) and to correlate this ID with Cmin in patients treated with voriconazole or posaconazole. Methods: The bioassay determined the ID for Candida parapsilosis using a disk diffusion method. Calibration curves were built for posaconazole and voriconazole in water and in 45% plasma. ID was determined in plasma from patients currently undergoing TDM for posaconazole (n = 73) or voriconazole (n = 90). Results: In water or plasma spiked with antifungals and patient samples, cubic regression between ID and Cmin gave coefficient of determination values of 0.997, 0.999, and 0.819, respectively, for posaconazole and 0.996, 0.990 and 0.925, respectively, for voriconazole (P < 0.001 for each curve). Calibration curves with or without plasma did not differ. For voriconazole, Cmin of 1 and 4.7 mg/L corresponded to 54% and 90% of maximal ID, respectively. For posaconazole, Cmin of 0.5, 0.7, and 1 mg/L corresponded to 26%, 40%, and 53% of maximal ID, respectively. Conclusions: Bioassay could be useful to better characterize the antifungal therapeutic range and brings additional information to the interpretation of TDM in patients for whom Cmin alone is insufficient to adjust the antifungal dosage.

Inflammation is the main risk factor of voriconazole overdose in hematological patients

Aim: Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Methods: Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/l; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using non-parametric or Chi-square tests followed by multivariable analysis. Results: VRC overdoses were significantly associated with high CRP and bilirubin levels, intra-venous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a genetic score1) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/l) was the sole independent risk factor of VRC overdose (p < 0.01). Patients with CRP levels > 96 mg/l had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/l. Conclusion: This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.

Cysteinyl-leukotriene pathway as a new therapeutic target for the treatment of atherosclerosis related to obstructive sleep apnea syndrome

Graphical abstract Figure. No caption available. Aims: Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl‐leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA‐related atherosclerosis. Methods and results: Determinants of the urinary excretion of LTE4 (U‐LTE4) including history of cardiovascular events, polysomnographic and biological parameters were studied in a cohort of 170 OSA patients and 29 controls, and in a subgroup of OSA patients free of cardiovascular event (n = 136). Mechanisms linking IH, the CysLT pathway and atherogenesis were investigated in Apolipoprotein E deficient (ApoE−/−) mice exposed to 8‐week IH. In the whole cohort, U‐LTE4 was independently influenced by age, minimal oxygen saturation, and a history of cardiovascular events, and correlated significantly with intima‐media thickness. In the subgroup of OSA patients free of cardiovascular event, increased U‐LTE4 was increased compared to controls and independently related to hypoxia severity and traditional risk factors aggregated in the 10‐year cardiovascular risk score of European Society of Cardiology. In IH mice, atherosclerosis lesion size and mRNA levels of 5‐lipoxygenase, 5‐lipoxygenase activating protein (FLAP) and CysLT1 receptor were significantly increased. This transcriptional activation was associated with the binding of HIF‐1 to the FLAP promoter and was strongly associated with atherosclerosis lesion size. CysLT1 receptor antagonism (montelukast) significantly reduced atherosclerosis progression in IH mice. Conclusions: IH‐related CysLT pathway activation contributes to OSA‐induced atherogenesis. In the era of personalized medicine, U‐LTE4 may be a useful biomarker to identify OSA patients for whom CysLT1 blockade could represent a new therapeutic avenue for reducing cardiovascular risk.

Inflammation is a potential risk factor of voriconazole overdose in hematological patients

Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case–control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/L; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using nonparametric or chi‐square tests followed by multivariable analysis. VRC overdoses were significantly associated with high CRP and bilirubin levels, intravenous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a combined genetic score) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/L) was the sole independent risk factor of VRC overdose (P < 0.01). Patients with CRP levels > 96 mg/L) had a 27‐fold (IC 95%: [6–106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/L. This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.

Could the thromboxane A2 pathway be a therapeutic target for the treatment of obstructive sleep apnea-induced atherosclerosis?

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of intermittent hypoxia. This disease is associated with premature atherosclerosis and consequently with increased cardiovascular morbidity and mortality. Atherosclerosis is a chronic inflammatory disease characterized by the activation of some components of the cyclooxygenase pathway. In particular, OSA is associated with activation of the thromboxane A2 (TXA2)-pathway, in which obesity seems to be a major confounding factor. Moreover, TXA2-pathway activation is related to the vascular remodeling associated with OSA. In view of the modest effect of the conventional treatment of OSA by continuous positive airway pressure on the cardiovascular risk in obese OSA patients, the identification of new therapeutic targets to treat OSA-induced atherosclerosis seems essential. As disruption of the TXA2-pathway has been suggested to be of potential interest to prevent atherosclerosis progression, we have reviewed the recent findings on the intricate interaction between the TXA2-pathway, chronic intermittent hypoxia and atherosclerosis and suggest promising therapeutic strategies to treat OSA-related atherogenesis, including pharmacological and/or nutritional approaches.