[Treatment of stable COPD : GOLD 2017 and the associations ]. / Traitement de fond de la BPCO : GOLD 2017 et les associations .

GOLD 2017 Report highlights the importance of patient symptoms and exacerbation risks in influencing some therapeutic decisions for individualized patient care. Assessment of the severity of airway obstruction is now separated from the " ABCD " groups but remains a key step for the diagnosis, prognostication and nonpharmacological therapies of COPD patients. Inhaled long-acting bronchodilators, alone or in combination, have a central role in the treatment of COPD patients. Their prolonged action allows a significant improvement not only of FEV1, but also of dyspnoea and health status. A clinically important effect was more frequently reached with LABA+LAMA combination than with either medication alone. LAMAs have a greater effect on exacerbation reduction compared to LABAs and LABA+LAMA combination reduces exacerbations compared to monotherapy or LABA+ICS combination. As regular treatment with ICS increases the risk of pneumonia, LABA+ICS combination is not a primary choice excepted in selected cortico-sensitive patients. When appropriate, withdrawal of ICS is achievable without significant harm using LABA+LAMA combination. Studies determining the precise place of LABA+LAMA+ICS combination in the treatment strategy are underway.

La révision 2017 des recommandations GOLD introduit ce qui peut être vu comme un changement de paradigme dans le traitement des patients BPCO stables. L'état de santé et la prévention d'évènements aigus (exacerbation, hospitalisation, décès) prennent le pas sur la spirométrie dans l'approche pharmacologique de ces patients. Ce changement se reflète dans la définition et le classement des patients. Les groupes ABCD sont maintenant basés exclusivement sur les symptômes et les exacerbations ; l'évaluation de la sévérité de l'obstruction bronchique reste nécessaire à l'établissement du diagnostic et du pronostic, ainsi qu'au traitement non-pharmacologique des patients, mais n'intervient plus dans l'algorithme décisionnel du traitement pharmacologique. Ce traitement pharmacologique réserve une place importante aux bronchodilatateurs de longue durée d'action et à leur association. Ils apportent une bronchodilatation couvrant le nycthémère, améliorant la dyspnée et la qualité de vie des patients. Un nombre plus important de patients atteignent une amélioration jugée cliniquement importante avec l'association LABA+LAMA qu'avec les monothérapies bronchodilatatrices. Le LAMA reste une molécule de choix dans la prévention des exacerbations et l'association LABA+LAMA permet une réduction moyenne plus importante du risque d'exacerbations que l'association LABA + ICS. Comme cette association augmente de manière significative le risque de pneumonie, l'utilisation de l'association LABA+ICS n'est plus conseillée en premier choix que chez des patients cortico-sensibles. Chez les patients pour qui cette association contenant un corticoïde topique n'est plus un premier choix, le passage vers l'association LABA+LAMA est possible sans augmentation significative du risque d'exacerbation. La place de la triple association LABA+LAMA+ICS reste à déterminer.

An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress.

Metformin (dimethylbiguanide) is an antihyperglycemic agent used in type 2 diabetes. Beyond its action on glycemic control, metformin exhibits other intrinsic effects that could play a role in prevention against diabetes complications. Some studies thus reported an improvement in the antioxidant status in patients treated with metformin. This might be in part related to its property to limit formation of advanced glycation end products (AGEs) and to decrease the overproduction of free radicals in diabetic subjects. The aim of this study was to investigate the in vitro ability of metformin to modulate the action of reactive oxygen species (ROS) generated either by water gamma radiolysis or by stimulated human leukocytes. Our results showed that metformin at pharmacologically relevant concentrations was in vitro able to scavenge hydroxyl ((.)OH) but not superoxide (O(.-)(2)) free radicals and that hydrogen peroxide did not react with metformin. Nevertheless, when polymorphonuclear cells (PMN) are stimulated by phorbol myristate acetate (PMA), or above all by formyl methionine leucyl phenylalanine (fMLP), a systematic (although nonsignificant) decrease of the ROS-induced chimiluminescence (CL) was observed. These results suggest that metformin could directly scavenge ROS or indirectly act by modulating the intracellular production of superoxide anion, of which NADPH oxidase constitutes the major source. This could contribute to the additional benefits of metformin, especially those related to the improvement in the cardiovascular outcomes in diabetes.

Standard treatment of alpha-tocopherol in Alagille patients with severe cholestasis is insufficient.

Alpha-tocopherol (alpha-T) is the most effective lipid-soluble antioxidant present in cells. We investigated the efficacy of alpha-T supplements for preventing lipid peroxidation in patients with Alagille syndrome, according to the severity of cholestasis. Patients were assigned to two groups on the basis of plasma bilirubin concentration (group I, bilirubin <100 microM; group II, bilirubin >100 microM). alpha-T concentrations were determined in plasma, in isolated lipoproteins, and in red blood cell membranes. In both groups of patients, alpha-T concentrations in plasma were similar to those in control subjects, but the distribution of alpha-T in lipoproteins was affected by the abnormal lipoprotein pattern in these patients. The efficacy of alpha-T was estimated by determining the amount of hydroperoxide produced from phosphatidylcholine and phosphatidylethanolamine (PE) molecular species owing to oxidative stress induced by lipoxygenase treatment. The concentrations of phosphatidylcholine molecular species and its corresponding hydroperoxides were significantly higher in both groups of patients. In group I, alpha-T and PE molecular species concentrations were similar to those in control subjects, but PE hydroperoxide concentrations were higher than those in the control subjects. In group II, alpha-T concentration was significantly lower and the concentrations of some PE molecular species and all PE hydroperoxides were lower than those in the control subjects. In conclusion, erythrocyte membrane alpha-T concentration was significantly lower only in patients with severe jaundice, despite alpha-T supplementation, raising the question as to whether the usual treatment was appropriate in this group.

Characterization of the trabecular rat bone mineral: effect of ovariectomy and bisphosphonate treatment.

Bisphosphonates, potent inhibitors of bone resorption, have been used clinically to correct the continued loss of bone mass in osteoporosis and in other conditions. However, there has been some concern that long-term treatment with these compounds, as well as more recently developed drugs, may also decrease the rate of bone formation. Bisphosphonates, which are strongly bound to hydroxyapatite crystals, may alter the structure and reactivity of the crystals, interfere with new crystal nucleation and growth, as well as alter the short-range order of newly formed crystals. We have investigated the chemistry and structure of the solid calcium-phosphate mineral phase of lumbar vertebrae of ovariectomized, 6.5-month-old rats treated with bisphosphonates for 1 year after onset of osteopenia. Appropriate control groups were used for comparison. The techniques used to assess the mineral phase were chemical analyses, Fourier transform-infrared (FT-IR) and FT-Raman spectroscopy, FT-IR microspectroscopy, and phosphorus-31 magic-angle-sample spinning nuclear magnetic resonance spectroscopy ((31)P MAS NMR). The (31)P MAS NMR spectra of trabecular bone of lumbar vertebrae of control, ovariectomized, and treated animals were similar. However, there were several significant differences in the results obtained by FT-IR spectroscopy of the whole tissue samples, FT-IR microspectroscopy of sections of bone, and chemical analyses. For example, whereas chemical analyses demonstrated that the CO(3) content of the mineral phase of the ovariectomized animals was decreased compared with controls, FT-IR microspectroscopy of bone sections showed no changes in the relative CO(3) content, but some changes in the environment of the CO(3) groups. However, chemical analyses of the crystals, combined with data from all three spectroscopic methods and with data from serum analysis, did indicate small changes in the mineral phase after ovariectomy, corrected after treatment with bisphosphonates. In any event, the chemical and structural data in the present studies demonstrate that the bisphosphonate, tiludronate, does not significantly alter the mineral components of bone after 1 year of treatment during the course of which bone loss was reversed.

Modulation of PAF production by incorporation of arachidonic acid and eicosapentaenoic acid in phospholipids of human leukemic monocyte-like cells THP-1.

Stimulated leukocytes generate platelet-activating factor (PAF) from membrane 1-O-alkyl-2-acyl-sn-glycerophosphocholine through hydrolysis of fatty acid and subsequent acetylation at the sn2 position of glycerol. Since the enzymes involved in the hydrolysis step of PAF biosynthesis have relative selectivity for arachidonic acid (AA), the fatty acid composition of PAF precursors might modulate PAF production. We studied the effect of AA and eicosapentaenoic acid (EPA) incorporation on PAF biosynthesis, by measuring the incorporation of [(3)H]acetate, in Ca(2+) ionophore (A23187)-stimulated human leukemic monocyte-like cells, THP-1. Supplementation of THP-1 with AA (25 microM, 1 week) or EPA (25 microM, 1 week) led to their efficient incorporation, in comparable quantities and with similar distributions, into phosphatidylcholine and phosphatidylethanolamine, and to a lesser extent into phosphatidylinositol. THP-1 cells supplemented with AA or with EPA synthetized similar amounts of PAF and of acyl analog of PAF under resting condition. However, AA-supplemented cells responded to A23187 stimulation by important raises of PAF (+125.71%) and of acyl analog of PAF (+381.75%) productions, whereas the same stimulation had little effect or no effect at all in cells supplemented with EPA. These results show that both EPA and AA may influence PAF production through their incorporation into PAF precursors, indicating that PAF production might be modulated by the fatty acid composition of its precursors.

Modulation of platelet-activating-factor production by incorporation of naturally occurring 1-O-alkylglycerols in phospholipids of human leukemic monocyte-like THP-1 cells.

1-O-Alkylglycerols (alkyl-Gro), naturally occurring compounds abundant in shark liver oil, protect patients from radiotherapy side-effects. However, the protection mechanism is not well understood. It might be mediated by alkyl-Gro incorporation into pools of platelet-activating factor (PAF) precursor and subsequent modification of PAF biosynthesis. Using a 3H-labelled or unlabelled natural alkyl-Gro mixture, in which prominent alkyl chains were C18:1(9) (54-65%), C16:1(7) (5-15.5%), and C16:0 (5-10%), we investigated the incorporation of alkyl-Gro into phospholipids of human leukemic monocyte-like THP-1 cells. Incubation of cells for 24 h with [3H]alkyl-Gro (10 microM) resulted in their incorporation into 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (1097+/-25.1 pmol/2x10(6) cells) and into 1-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine (640.4+/-12.5 pmol/2x10(6) cells) with a total yield of 6.5%. Such incorporation induced production of 1-O-[3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine ([3H]PAF), which was increased after stimulation by the calcium ionophore A23187. HPLC analysis of the [3H]PAF molecular species indicated that the three major [3H]alkyl-Gro were used for [3H]PAF synthesis in ratios similar to that of the mixture. Total production of biologically active PAF, as measured by the platelet-aggregation bioassay, was also increased by alkyl-Gro incorporation in resting (+20%) and in A23187-stimulated (+59%) THP-1 cells. HPLC analysis of the [3H]PAF produced in the presence of [3H]acetate, confirmed that levels of PAF, but not of its 1-acyl analog, were increased by alkyl-Gro incorporation in resting and stimulated cells. However, the rise in [3H]acetyl-PAF, which resulted mainly from C16:0 PAF, was reduced by about 50% in the presence of the PAF-receptor antagonist SR 27417, providing evidence that stimulation of total PAF synthesis was caused by the increase in the precursor pool and autocrine amplification of PAF-induced PAF production. Thus, the supplementation of THP-1 cells in culture with naturally occurring alkyl-Gro led to the incorporation of alkyl-Gro into ether-containing phospholipids, which were subsequently used for PAF synthesis. Furthermore, alkyl-Gro incorporation resulted in a significant rise in PAF production by THP-1 cells under resting and stimulated conditions. These results may be of importance for modulating PAF production in several pathophysiological conditions, such as peroxysome deficiencies, that are associated with a lack of ether lipid synthesis.

Ciguatoxin, extracted from poisonous morays eels, causes sodium-dependent calcium mobilization in NG108-15 neuroblastoma x glioma hybrid cells.

Measurement of intracellular Ca2+ concentration ([Ca2+]i) in cultured mouse NG108-15 neuroblastoma x glioma hybrid cells, using the fluorescent probe fura-2, revealed that 5-25 nM ciguatoxin (CTX) increased [Ca2+]i either in cells bathed in standard medium or after removal of external Ca2+ by a Ca(2+)-free medium supplemented with EGTA. Tetrodotoxin prevented the CTX increased [Ca2+]i suggesting that CTX-induced mobilization of intracellular Ca2+ depends on Na+ influx through voltage-gated Na channels. CTX-induced Ca2+ mobilization prevented subsequent action of bradykinin (1 microM) suggesting that CTX stimulates the inositol 1,4,5-trisphosphate-releasable Ca2+ store.

Anti-inflammatory activity of a dual inhibitor of cyclooxygenase and lipoxygenase pathways, CBS-1108 (2-acetylthiophene-2-thiazolylhydrazone).

Anti-inflammatory therapy is actually devolved to glucocorticoids which prevent the release of arachidonic acid from phospholipids and consequently its subsequent transformation into prostaglandins and leukotrienes. This activity explains in part why steroids are better anti-inflammatory agents than acetylsalicylic acid (ASA)-like drugs which only reduce prostaglandin production. Despite their superior therapeutic actions, there are many side effects associated with corticosteroids. Therefore in recent years, research of non-steroid dual inhibitors of prostaglandin and leukotriene production has been developed. The present paper investigates the pharmacological activity of such a new compound, CBS-1108 (2-acetylthiophene-2-thiazolylhydrazone), in comparison with dexamethasone, cyclooxygenase inhibitors (ASA and indomethacin) and reference dual inhibitors (nordihydroguaiaretic acid (NDGA) and 3-amino-1-(m-trifluoromethylphenyl)-2-pyrazoline (BW-755 C]. The two-pathway inhibitors and ASA-like drugs are similarly effective on paracentesis-induced disruption of the blood-aqueous barrier and on croton oil-induced ear edema. On the contrary in an animal model of leukocyte migration and on mast cell degranulation, NDGA and CBS-1108 are very active when the other tested compounds are inefficient.

[Assay of serum selenium by atomic absorption spectrophotometry. Value in the biological diagnosis of nonobstructive cardiomyopathies]. / Dosage du sélénium sérique par spectrophotométrie d'absorption atomique. Intérêt dans le diagnostic biologique des cardiomyopathies non obstructives.

The authors present a technique of direct assay of serum selenium by atomic absorption spectrophotometry, using electrothermal atomization in a graphite oven. The initial results of the assays performed in patients with non-obstructive cardiomyopathies (NOCM) reveal a decrease in the serum selenium level. This element could therefore represent a laboratory marker for these diseases.

[A simple method for evaluation of the lecithin/sphingomyelin ratio in amniotic fluid. Variation in normal and abnormal pregnancies (138 cases) (author's transl)]. / Evaluation simple du rapport lécithines/sphingomyélines du liquide amniotique. Variations au cours des grossesses normales et pathologiques (a propos de 138 cas)

The determination of the lecithin/sphingomyelin ratio in amniotic fluid is a useful index for assessing fetal pulmonary maturity. The authors propose a simple and specific method : the amniotic lipids are extracted and thin layer chromatography is carried out in an acetic acid containing medium. The L/S ratio was studied and discussed in 138 normal and pathological cases.