[Screening for familial hypercholesterolemia from low-density lipoprotein cholesterol levels at admission in the coronary care unit]. / Dépistage de l'hypercholestérolémie familiale à partir du LDL cholestérol à l'admission en unité de soins intensifs cardiologiques.

BACKGROUND: Familial hypercholesterolemia (FH) is a frequent genetic disorder that leads to premature atherosclerosis and coronary artery disease. However, knowledge of FH by cardiologists is weak, and FH remains underdiagnosed in France. FH should be suspected when low-density lipoprotein cholesterol (LDLc) levels exceed 1.9g/L (4.9mmol/L) without lipid lowering therapy. PURPOSE: This multicenter retro- and prospective observational study aimed at estimating the prevalence of high LDLc levels in patients admitted in coronary care units, and the impact for the personal and familial follow-up for lipid status. METHODS: Retrospective analysis of all plasma lipid measurements performed at admission in coronary care unit of 4 hospitals in 2017. Retrospective analyses of demographic, clinical, and coronary data of consecutive patients with LDLc levels≥1.9g/L. Prospective 1 year follow-up focused on lipid levels, treatments, and personal and familial screening for FH. RESULTS: Lipid measurement has been performed in 2172 consecutive patients, and 108 (5%) had LDLc level≥1.9g/L (mean age 64±14 years, men 51%). The primary cause of the hospitalisation was acute coronary syndrome (78%), and 22% of patients were free off coronary artery disease. Lipid lowering therapy was present in 9% of patients at admission, and 84% at discharge, with high statins regimen. At 1-year follow-up, control of LDLc level was not performed in 20% of patients, and statin dose was decreased (36%) or withdrawn (7%) in 43%. Lipid measurement has been performed in at least one first degree relative in 37% of patients, and genetic exploration has been done for 3 patients. CONCLUSIONS: Screening of FH in CCU should be routinely performed using the Dutch Score when LDLc is above 1.9g/L. Individual and familial management of patients at high risk for FH screened in CCU should be optimized, both for diagnosis and therapeutic purposes.

Effects of okadaic acid on the human isolated bronchus.

The effects of okadaic acid, a polyether derivative of a 38-carbon monocarboxylic fatty acid obtained from a culture of the marine dinoflagellate, Prorocentrum lima, were studied on the human isolated bronchus. In low concentrations (0.01 and 0.03 microM), okadaic acid had no significant effect of its own on the human isolated bronchus, but in higher concentrations (0.1-10 microM) it induced a series of contractions and relaxations. The first contraction was of low intensity (5% of maximum response to acetylcholine 3 mM) and occurred early. The second contraction had a higher amplitude (30% of maximum response to acetylcholine 3 mM) and reached its peak with okadaic acid 0.3 microM. At higher concentrations (1-10 microM), following a relaxation phase, a later rebound contraction occurred between 70 and 120 min and corresponded to 40% of the maximum response to acetylcholine 3 mM. In addition, okadaic acid inhibited or abolished the contractile response evoked by either KCl 60 mM or acetylcholine 3 mM with IC50 of 0.04 and 0.12 microM, respectively. The second contraction evoked by 0.3 microM okadaic acid was partially inhibited in the presence of the Ca2+ channel blocker, nicardipine 1 microM, or after incubation of the human bronchus in a Ca(2+)-free solution and it was completely abolished in the presence of CdSO4 0.1 mM.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolation and purification of three glucuronides of antipyrine. Proposal for an original analytical method for quantitation of sulpho- and glucuroconjugated metabolites.

The determination of the concentrations of antipyrine metabolites in biological fluids is hampered by the difficulty in obtaining pure conjugated compounds to be used as standards. Most authors have proposed determination of total forms by high performance liquid chromatography (HPLC) after deconjugation of these metabolites using chemical or enzymatic hydrolysis. Up to now there is no satisfactory hydrolysis method for the study of all antipyrine metabolites. The situation is further complicated by the fact that the deconjugated metabolites are highly unstable whichever technique is being used. Because of the lack of stability of all these molecules it has been necessary to isolate the glucuroconjugated compounds from urine. We describe a method which allows us to obtain highly purified glucuroconjugated metabolites of antipyrine. Sulphoconjugated compounds have been synthesized previously. We are thus able to propose a chromatographic procedure which allows us to determine simultaneously all stable phase I and phase II metabolites of antipyrine in biological fluids without any step of extraction. This analytical technique allows us to study the activity of the different isoenzymes implicated in the metabolism of antipyrine.

Determination of antipyrine sulphoconjugates in isolated cultured rat hepatocytes.

1. An analytical method for the simultaneous determination of three major metabolites of antipyrine, namely, 3-hydroxymethylantipyrine (phase I), 4-hydroxyantipyrine sulphoconjugate (phase II) and norantipyrine sulphoconjugate (phase II) in cultured rat hepatocytes has been developed and applied to the study of induction or inhibition of these metabolic pathways following pretreatment of rats with several inducers or inhibitors. 2. Phenobarbital was the most effective inducer of the three pathways studied, particularly the formation of 4-hydroxyantipyrine sulphoconjugate; 3-methyl-cholanthrene (MC) increased the formation of the two sulphoconjugates, but decreased the formation of 3-hydroxymethylantipyrine. 3. Rifampicin inhibits antipyrine metabolism in rat. The three metabolic pathways studied were decreased by 30%. 4. SKF 525A markedly inhibited the three metabolic pathways; piperonyl butoxide and omeprazole decreased the three pathways but to a lesser extent. Cimetidine decreased the two sulphoconjugates pathways, but did not affect 3-hydroxymethylantipyrine formation.

Separation and identification of the 4-hydroxyantipyrine sulphoconjugate.

In a previous study we observed, during separation of total antipyrine metabolites by high-performance liquid chromatography and after enzymatic hydrolysis, an unidentified peak corresponding to an ionic compound with pyrazolinone features. In the present study, this compound was identified as the 4-hydroxyantipyrine sulphoconjugate, and its structure was definitively confirmed by gas chromatographic-mass spectrometric analysis and by the use of pure synthetic substance. We also demonstrated the inhibitory effect of sodium metabisulphite, a necessary preservative of urinary samples, on hydrolysis of this conjugate in the presence of sulphatases from Helix pomatia or Aerobacter aerogenes. This inhibitory effect makes it impossible to perform a global assay of antipyrine metabolites after enzymatic or chemical hydrolysis and confirms the value of direct assay of the 4-hydroxyantipyrine sulphoconjugate.

High-performance liquid chromatographic method for the determination of the three main oxidative and 3-carboxylic antipyrine metabolites in human urine.

The oxidative metabolism of xenobiotics is usually explored using the antipyrine test, which consists of determining the production clearances and urinary percentages of three major antipyrine metabolites 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine. The total forms of these compounds are generally determined by high-performance liquid chromatography (HPLC). However, the 3-carboxylic acid metabolite (3-carboxyantipyrine), which is the ultimate oxidation form in the 3-hydroxylation pathway, should also be taken into account, but so far its determination by HPLC has not been reported. A simple and accurate HPLC method has now been developed to determine the three major metabolites plus 3-carboxyantipyrine. In this method, all compounds are extracted in an aprotic non-polar solvent, at pH 3.5 for the major metabolites and unchanged antipyrine, then at pH 0.9 for 3-carboxyantipyrine. Total forms are evaluated after enzymatic hydrolysis. Throughout the procedure, attention is paid to the relative instability of norantipyrine and 4-hydroxyantipyrine. Recovery, accuracy and precision are discussed. The method has been applied to the determination of relative amounts (percentage of the dose administered) excreted in the urine of ten adult subjects 48 h after ingestion of antipyrine (600 mg). The proportion of 3-carboxyantipyrine excreted was 4.5 +/- 0.2%, which is in agreement with published values obtained by gas chromatography. The excretion rates of the major metabolites also were similar to those reported in the literature, thereby confirming that the reported method is valid. 3-Carboxyantipyrine is totally excreted as the free form and norantipyrine almost completely as glucuroconjugate.