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Patients at high or very high cardiovascular risk should have a LDL cholesterol level as low as possible, a target that may be difficult to be reached with statin monotherapy, especially when this treatment is not well tolerated. It is generally recommended to use pharmacological combinations to reach more and more strict objectives. Bempedoic acid is a new oral cholesterol-lowering medication that reduces hepatic cholesterol synthesis by inhibiting the enzyme adenosine triphosphate (ATP)-citrate lyase enzyme. Because this medication is a prodrug that is selectively activated in the liver, it is deprived of any muscular adverse effect. This article summarizes the mode of action, pharmacokinetics, efficacy, safety profile, indications and reimbursement conditions of bempedoic acid. This novel cholesterol-lowering drug is indicated in combination with statins (with or without ezetimibe) in patients who do not attain LDL goals despite administration of a statin at the maximum tolerated dose or in case of statin intolerance.Les patients à haut ou très haut risque cardiovasculaire doivent avoir une concentration de cholestérol LDL la plus basse possible, parfois difficile à atteindre avec les statines en monothérapie, a fortiori si celles-ci sont mal tolérées. Il est généralement recommandé de recourir à des combinaisons pharmacologiques pour atteindre les objectifs de LDL de plus en plus stricts. L’acide bempédoïque est un nouvel agent hypocholestérolémiant actif par voie orale qui réduit la synthèse hépatique de cholestérol en inhibant l’adénosine triphosphate (ATP)-citrate lyase. Comme ce médicament est une prodrogue activée sélectivement dans le foie, il est dénué d’effet indésirable dans les cellules musculaires. Cet article résume le mode d’action, la pharmacocinétique, l’efficacité, le profil de sécurité, les indications et les conditions de remboursement de l’acide bempédoïque. Ce nouvel hypocholestérolémiant est indiqué en combinaison avec les statines (avec ou sans ézétimibe) chez les patients n’atteignant pas les objectifs en termes de LDL malgré une statine administrée à la dose maximale tolérée ou en cas d’intolérance aux statines.

Last European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines on dyslipidemia published in 2019 recommend an LDL-cholesterol goal1.4 mmol/l (55 mg/dl) for people at very high cardiovascular risk. They propose combinations of lipid lowering therapies in addition to statins if necessary to meet this objective, which is very rarely reached in this at risk population. Two new drugs have recently received European Medicines Agency (EMA) approval for the treatment of hypercholesterolaemia, bempedoic acid, a small oral molecule that inhibits hepatic cholesterol synthesis, and inclisiran, a small interfering RNA that reduces PCSK9 levels after its subcutaneous injection. This article summarizes the mode of action, efficacy data, safety/tolerance profile and indications of these two innovative drugs.Les recommandations de 2019 de l’European Society of Cardiology et de l’European Atherosclerosis Society pour le traitement des dyslipidémies préconisent un cholestérol lipoprotéine de basse densité (LDL)1,4 mmol/l (55 mg/dl) chez les sujets à très haut risque cardiovasculaire. Elles proposent des associations de médicaments hypolipémiants en addition aux statines pour rencontrer cet objectif, souvent non atteint dans cette population. Deux nouvelles médications ont reçu l’approbation de l’Agence européenne du médicament pour le traitement de l’hypercholestérolémie, l’acide bempédoïque, une médication orale qui réduit la synthèse hépatique de cholestérol, et l’inclisiran, un petit acide ribonucléique interférent qui réduit les concentrations de proprotéine convertase subtilisine/kexine de type 9. Nous résumons le mode d’action, les données d’efficacité, le profil de sécurité et les indications de ces deux classes thérapeutiques innovantes.

In the last 10 years, numerous studies have been published that throw new light on rosacea, in all areas of the disease. This overview summarises all the key developments, based on the indexed bibliography appearing in Medline between 2007 and 2017. Recent epidemiological data show that the prevalence of the disease is doubtless greater than estimated hitherto (more than 10% of adults in some countries) and that we should not overlook rosacea in subjects with skin phototypes V or VI, a condition that exists on all continents. A new classification of rosacea by phenotype comprising major and minor signs has been put forward; it provides a more rational approach to suitable management based upon symptoms, the severity of which may be graded into 5 classes. The treatments with the best-demonstrated efficacy (updated Cochrane study) are topical metronidazole, azelaic acid and ivermectin, and oral doxycycline; isotretinoin is effective against resistant forms but is off-label. In ocular rosacea, the reference treatment is doxycycline in combination with topical therapy of the eyelids. The physiopathology is complex and involves several factors: vascular (vasodilatation, vascular growth factors), neurovascular (hypersensitivity, neuropathic pain, neuropeptides), infectious (Demodex folliculorum and its microbiota) and inflammatory (abnormal production of pro-inflammatory peptides of the innate immune system). In addition, there is a genetic predisposition as demonstrated by the weight of familial history and comparison of homozygous and heterozygous twins. There is also activation of several genes involved in immunity, inflammation and lipid metabolism; the theory of hydrolipid film anomalies has been posited once more. There has thus been a tremendous leap forward in the field of rosacea research, with therapeutic progress and improved understanding of the underlying mechanisms, which should enable the future development of more targeted treatments as well as global management of this disease, which has major social and emotional consequences on the life of patients.

Long-chain dicarboxylic acids (DCA) are intermediates of industrial interests (polymers, plastics, lubricants, antibiotics and fragrances) which are difficult to produce by chemical synthesis. The aim of this study is to develop a biotechnological process to produce these compounds by bioconversion of renewable raw material by the yeast Yarrowia lipolytica. In wild type yeast, fatty acids are degraded mainly through the Β-oxidation pathway. We blocked the Β-oxidation pathway by disruption of the six genes which code the acyl-CoA oxydases thus allowing to reorientate the fatty acids flux towards the ω-oxidation which led to the production of DCA. Further, the improvement of DCA production was obtained by increasing the hydroxylation activity, involved in the first stage of ω-oxidation, by overexpression of genes coding the NADPH cytochrome P450 reductase and the 12 P450 cytochromes. Nevertheless, half of the bioconversion substrate was accumulated in the cytoplasmic lipid bodies. This storage was decreased, by the disruption of two genes, DGA1 and LRO1, involved in this pathway, thus allowing an increase in the bioconversion yield. Finally, the study of insertion mutants revealed an involvement of 5 ABC transporter of the PDR type family which confer pleiotropic drug resistance. The functional study of this family suggested that the ABC transporter coded by ABC1 gene was a membrane exporter specific for long chain alkanes and represents the first ABC transporter of the PDR type identified responsible for the export of physiological molecules. Overall, this work has provided the development of a genetically modified strain of Y. lipolytica to produce DCA from vegetable oils.; Les acides dicarboxyliques (DCA) sont des composés de base pour la production de polymères, plastiques, lubrifiants, antibiotiques et parfums. Bien que de grand intérêt, les DCA qui comportent une chaîne aliphatique supérieure à douze atomes de carbone sont difficilement synthétisables par la voie chimique. L'objet de cette étude est de développer un procédé biotechnologique pour produire ces composés par bioconversion de matières premières renouvelables (huile de tournesol oléique) via la levure Yarrowia lipolytica. Chez les souches sauvages, les acides gras sont principalement dégradés par la voie de la Β-oxydation. Nous avons bloqué la première étape de la Β-oxydation par disruption séquentielle des six gènes codant les acyl-CoA oxydases permettant ainsi de réorienter le flux d'acides gras vers l'ω-oxydation qui conduit à la production de DCA. L'amélioration de la production des DCA a été obtenue par l'augmentation de l'activité d'hydroxylation, impliquée dans l'ω-oxydation, en surexprimant les gènes codant la NADPH cytochrome P450 réductase et les 12 cytochromes P450. Néanmoins, la moitié du substrat s'accumule dans les corps lipidiques. Ce stockage a été réduit, par disruption de gènes, entraînant ainsi une augmentation du rendement de bioconversion.Enfin, l'étude de mutants d'insertion a révélé l'implication de 5 ABC transporteurs PDR qui confèrent la résistance aux drogues. L'étude fonctionnelle de cette famille a démontré que le transporteur Abc1p serait un exporteur membranaire spécifique des alcanes à longue chaîne carbonée, constituant le premier ABC transporteur PDR responsable de l'export de molécules physiologiques. Ces travaux ont permis de développer une souche améliorée de Y. lipolytica pour la production de DCA à partir d'huiles végétales.

In non-insulin-dependent diabetes, site-specific defects of glucose metabolism in the pancreatic B-cell may account for a preferential alteration of its secretory response to the hexose. A novel therapeutic approach could thus be based on the use of non-glucidic nutrients that would bypass the metabolic defect in the islets of diabetic subjects. In this respect, the esters of mitochondrial dicarboxylic acids, such as succinic or glutamic acid, offer the advantage of being well transported into the islet cells and, hence, of stimulating efficiently both proinsulin biosynthesis and insulin release.

We have investigated the effect of dicarboxylic lecithins on liposomes prepared from egg-lecithins and their incorporation into liposome preparation. In the presence of phospholipids, liposome cell permeability to glucose is five times higher than in controls. The incorporation of dicarboxylic lecithins into liposomes at a molar concentration of 50 molecules per cent reduces by 60% the amount of glucose trapped inside the liposomes. Measurements of ovolecithin-glutaryl-lecithin liposomes stability show that stable structures are formed at a molar concentration of 70 molecules per cent in the presence of cholesterol. On the contrary, the liposomes prepared in the absence of cholesterol are not stable at a molar concentration of 50 molecules per cent. Measurements of sedimentation of mixed dispersions of monocarboxylic lecithins and glutaryl-lecithins show that glutaryl-lecithins must be in the form of micelles to solubilize the phosphatidyl cholines.

Reye's syndrome (RS) has been defined by the CDC as an acute non-inflammatory encephalopathy and hepatopathy, with no reasonable explanation for the cerebral and hepatic abnormalities. The diagnosis of RS is made by a constellation of clinical and laboratory features, none of which are pathognomonic. The demonstration of a fatty infiltration on liver biopsy is not really specific. On the other hand, the mitochondrial ultrastructural abnormalities appear to be characteristic of RS. Cerebral edema with intracranial hypertension represents the most immediate threat to life, the cause of the encephalopathy being unknown. The treatment of RS consists in perfusion of hypertonic glucose solution and management of intracranial hypertension. Grade I RS should be recognized early and treated with intravenous glucose. A number of metabolic disorders may yield a clinical picture resembling RS. These include disturbances of organic acid metabolism, urea cycle defects, and disorders of carbohydrate metabolism. The pathogenesis of RS is a mitochondrial insult induced by different viruses, drugs, exogenous toxins, and genetic factors. In the USA, pilot studies showed that a majority of RS cases may be attributable to salicylate use. In France, RS remains unfrequent although no precise epidemiological data are available. An epidemiological study appears therefore necessary for a better understanding of this mysterious syndrome. There is a need for a biological marker of the mitochondrial injury.

The medium chain acyl-CoA deshydrogenase defect: a new inherited metabolic disorder. This enzymatic defect blocks the catabolism of non esterified fatty acids during fasting. Thus, this disease is revealed by a coma due to hypoglycemia in a young child; the presence of dicarboxylic aciduria in such a situation is the main evidence for this diagnosis. Finally, the enzymatic studies performed on skin fibroblasts show a defect in medium chain acyl-CoA deshydrogenase. When a child is investigated away from a coma episode, the ketotic diet induces dicarboxylic aciduria but must be performed in an intensive care unit for its dangers.

We shall distinguish the case of non aromatic organic acids from that one of phenolic acids. In the first one, we have applied to wines a method used for fruit-juices by Palmer and List, 1973. After contact of the wine with a strong acid resin, its is injected on anion exchange resin Aminex A 25 precolumn (formiate form) which retains all the organic acids. The precolumn is washed with water to eliminate neutral components, then connected with the chromatographic column which contains the same resin. The different acids are eluted with a solution of natrium formiate at 70 degrees C. They are detected by differential refractometry (galacturonic, lactic, malic, succinic, tartric acids) and by ultraviolet at 254 nm (shikimic acid). Beside these compounds which are identified by their retention volumes, others not yet attributed peaks are detected. The limits of detection are 2 mg/l for shikimic acid, 30 mg/l for tartric acid and 15 mg/l for the others. Analysis time is about one hour. In the case of phenolic acids, we extract them from wine by diethyl ether after saturation with NaCl or by demixtion. The determination of phenolic acids is done on the ether extract or on the organic layer of the demixtion. Chromatography is obtained on octadecylsilanised column (RP 18) with solvent gradient (from 10% methanol in KH2PO4O,1 M pH 2,1 to 60% methanol in the same buffer) and detection in ultraviolet at 254 nm. The knowledge of recovery of acids by diethyl ether or by demixtion permits to obtain their concentrations in wine. The different so determinated phenolic acids are: gallic, 4 hydroxybenzoic, cafeic, vanillic, syringic and para coumaric acids. We have applied these methods to 32 wines for phenolic acids and 80 wines for non aromatic acids. Some results are presented in the case of 24 wines issued from Gamay and 8 wines from Pinot and it appears that tartric and shikimic acids have more important average concentrations in the former than in the latter.