Pharmacokinetic modeling of morphine and its glucuronides: Comparison of nebulization versus intravenous route in healthy volunteers

International audienc

Determination of Lipoxygenase, CYP450, and Non-Enzymatic Metabolites of Arachidonic Acid in Essential Hypertension and Type 2 Diabetes

Type 2 diabetes (T2D) and hypertension (HTN) are common risk factors of cardiovascular diseases (CVD) characterized by chronic low-grade systemic inflammation and impaired endothelial function. This study aimed to assess whether levels of non-enzymatic, lipoxygenase (LOX)- and cytochrome P450 (CYP)-derived arachidonic acid (ARA) metabolites, which are known regulators of vascular homeostasis, are affected by HTN and T2D. For this objective, 17 plasma level derivatives of ARA were quantitated by chromatography coupled with mass spectrometry in 44 patients (12 healthy, 8 HTN, 7 T2D, and 17 HTN + T2D). Effects of hyperglycemic and hyperinsulinemic clamps on ARA metabolite levels were assessed in seven healthy subjects. No significant differences in the plasma levels of ARA metabolites were observed for T2D patients compared with healthy volunteers. HTN was associated with an alteration of ARA metabolite correlation patterns with increased 20-, 19-, 15-, and 8-hydroxyeicosatrienoic acid (HETE). A decrease of 20-HETE was also observed during both hyperglycemic and hyperinsulinemic clamps. Additional experiments are needed to assess whether the modulation of HETE metabolites in HTN may be of interest. Furthermore, although not affected by T2D, it remains to investigate whether the decrease of 20-HETE observed during clamps may be related to the regulation of glucose tolerance and insulin signaling

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients

This study addressed the hypothesis that epoxyeicosatrienoic acids (EETs) synthesized by CYP450 and catabolized by soluble epoxide hydrolase (sEH) are involved in the maintenance of renal allograft function, either directly or through modulation of cardiovascular function. The impact of single nucleotide polymorphisms (SNPs) in the sEH gene EPHX2 and CYP450 on renal and vascular function, plasma levels of EETs and peripheral blood monuclear cell sEH activity was assessed in 79 kidney transplant recipients explored at least one year after transplantation. Additional experiments in a mouse model mimicking the ischemia-reperfusion (I/R) injury suffered by the transplanted kidney evaluated the cardiovascular and renal effects of the sEH inhibitor t-AUCB administered in drinking water (10 mg/l) during 28 days after surgery. There was a long-term protective effect of the sEH SNP rs6558004, which increased EET plasma levels, on renal allograft function and a deleterious effect of K55R, which increased sEH activity. Surprisingly, the loss-of-function CYP2C9*3 was associated with a better renal function without affecting EET levels. R287Q SNP, which decreased sEH activity, was protective against vascular dysfunction while CYP2C8*3 and 2C9*2 loss-of-function SNP, altered endothelial function by reducing flow-induced EET release. In I/R mice, sEH inhibition reduced kidney lesions, prevented cardiac fibrosis and dysfunction as well as preserved endothelial function. The preservation of EET bioavailability may prevent allograft dysfunction and improve cardiovascular disease in kidney transplant recipients. Inhibition of sEH appears thus as a novel therapeutic option but its impact on other epoxyfatty acids should be carefully evaluated

The effect of camelina oil on vascular function in essential hypertensive patients with metabolic syndrome: a randomized, placebo-controlled, double-blind study

International audienceBackground The effects of a dietary supplementation with the vegetable omega-3 α-linolenic acid (ALA) on cardiovascular homeostasis are unclear. In this context, it would be interesting to assess the effects of camelina oil. Objective This study aimed to assess the cardiovascular and metabolic effects of camelina oil in hypertensive patients with metabolic syndrome. Methods In a double-blind placebo-controlled randomized study, treated essential hypertensive patients with metabolic syndrome received during 6 months either cyclodextrin-complexed camelina oil containing ≈ 1.5 g ALA/day (n = 40), or an isocaloric placebo (n = 41), consisting in the same quantity of cyclodextrins and wheat starch. Anthropometric data, plasma lipids, glycemia, insulinemia, creatininemia, thiobarbituric acid reactive substances, high-sensitivity C-reactive protein, and n-3, n-6 and n-9 fatty acids in erythrocyte membranes were measured. Peripheral and central blood pressures, arterial stiffness, carotid intima-media thickness and brachial artery endothelium-dependent flow-mediated dilatation and endothelium-independent dilatation were assessed. Results Compared to placebo, camelina oil increased ALA (mean ± SD: 0 ± 0.04 vs. 0.08 ± 0.06%, P < 0.001), its elongation product eicosapentaenoic acid (EPA; 0 ± 0.5 vs. 0.16 ± 0.65%, P < 0.05), and the n-9 gondoic acid (0 ± 0.04 vs. 0.08 ± 0.04%, P < 0.001). No between-group difference was observed for cardiovascular parameters. However, changes in flow-mediated dilatation were associated with the magnitude of changes in EPA (r = 0.26, P = 0.03). Compared to placebo, camelina oil increased fasting glycemia (–0.2 ± 0.6 vs. 0.3 ± 0.5 mmol/L, P < 0.001) and homeostatic model assessment for insulin resistance (HOMA-IR; –0.8 ± 2.5 vs. 0.5 ± 0.9, P < 0.01) index, without affecting plasma lipids, or inflammatory and oxidative stress markers. Changes in HOMA-IR index were correlated with the magnitude of changes in gondoic acid (r = 0.32, P < 0.01). Nutritional intake remained similar between groups. Conclusion ALA supplementation with camelina oil did not improve vascular function but adversely affected glucose metabolism in hypertensive patients with metabolic syndrome Whether this adverse effect on insulin sensitivity is related to gondoic acid enrichment, remains to be elucidated

Reference values for local arterial stiffness. Part B: femoral artery

Carotid-femoral pulse wave velocity (PWV) is considered the gold standard measure of arterial stiffness, representing mainly aortic stiffness. As compared with the elastic carotid and aorta, the more muscular femoral artery may be differently associated with cardiovascular risk factors (CV-RFs), or, as shown in a recent study, provide additional predictive information beyond carotid-femoral PWV. Still, clinical application is hampered by the absence of reference values. Therefore, our aim was to establish age and sex-specific reference values for femoral stiffness in healthy individuals and to investigate the associations with CV-RFs

Reference values for local arterial stiffness. Part A: carotid artery

Non-invasive measures of common carotid artery properties, such as diameter and distension, and pulse pressure, have been widely used to determine carotid artery distensibility coefficient - a measure of carotid stiffness (stiffness ∼1/distensibility coefficient). Carotid stiffness has been associated with incident cardiovascular disease (CVD) and may therefore be a useful intermediate marker for CVD. We aimed to establish age and sex-specific reference intervals of carotid stiffness