Developing a model to predict the early risk of hypertriglyceridemia based on inhibiting lipoprotein lipase (LPL): a translational study

Hypertriglyceridemia; Inhibiting lipoprotein lipaseHipertrigliceridèmia; Inhibició de la lipoproteïna lipasaHipertrigliceridemia; Inhibición de la lipoproteína lipasaHypertriglyceridemia (HTG) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). One of the multiple origins of HTG alteration is impaired lipoprotein lipase (LPL) activity, which is an emerging target for HTG treatment. We hypothesised that early, even mild, alterations in LPL activity might result in an identifiable metabolomic signature. The aim of the present study was to assess whether a metabolic signature of altered LPL activity in a preclinical model can be identified in humans. A preclinical LPL-dependent model of HTG was developed using a single intraperitoneal injection of poloxamer 407 (P407) in male Wistar rats. A rat metabolomics signature was identified, which led to a predictive model developed using machine learning techniques. The predictive model was applied to 140 humans classified according to clinical guidelines as (1) normal, less than 1.7 mmol/L; (2) risk of HTG, above 1.7 mmol/L. Injection of P407 in rats induced HTG by effectively inhibiting plasma LPL activity. Significantly responsive metabolites (i.e. specific triacylglycerols, diacylglycerols, phosphatidylcholines, cholesterol esters and lysophospholipids) were used to generate a predictive model. Healthy human volunteers with the impaired predictive LPL signature had statistically higher levels of TG, TC, LDL and APOB than those without the impaired LPL signature. The application of predictive metabolomic models based on mechanistic preclinical research may be considered as a strategy to stratify subjects with HTG of different origins. This approach may be of interest for precision medicine and nutritional approaches.This research was financially supported by the Catalan Government through the funding grant ACCIÓ-Eurecat (PRIV2019-PREVENTOMICS) and by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TECNOMIFOOD project. CER-20191010

Synthesis and pharmacological characterization of the selective GluK1 radioligand (S)-2-amino-3-(6-[³H]-2,4-dioxo-3,4-dihydrothieno.3,2-d] pyrimidin1(2H)- yl) propanoic acid ([³H]-NF608)

The kainic acid receptors belong to the class of ionotropic glutamate receptors and comprise five subunits named GluK1-5. Radioligands are essential tools for use in binding assays aimed at ligand-receptor structure-activity-relationship studies. Previous work has led to the synthesis of GluK1 radioligands [3H]-SYM2081, [3H]-UBP310 and [3H]-ATPA, however all strategies were work-intensive and thus not attractive. Herein, we report the synthesis of [3H]-NF608 and subsequent pharmacological evaluation at homomeric recombinant rat GluK1 receptors. Binding affinities of a series of standard GluK1 ligands were shown to be in line with previously reported affinities obtained by use of already reported radioligands

Major differences in organization and availability of health care and medicines for HIV/TB coinfected patients across Europe

Objectives: The aim of the study was to investigate the organization and delivery of HIV and tuberculosis (TB) health care and to analyse potential differences between treatment centres in Eastern (EE) and Western Europe (WE). Methods: Thirty‐eight European HIV and TB treatment centres participating in the TB:HIV study within EuroCoord completed a survey on health care management for coinfected patients in 2013 (EE: 17 respondents; WE:21; 76% of all TB:HIV centres). Descriptive statistics were obtained for regional comparisons. The reported data on health care strategies were compared with actual clinical practice at patient level via data derived from the TB:HIV study. Results: Respondent centres in EE comprised: Belarus (n = 3), Estonia (1), Georgia (1), Latvia (1), Lithuania (1), Poland (4), Romania (1), the Russian Federation (4) and Ukraine (1); those in WE comprised: Belgium (1), Denmark (1), France (1), Italy (7), Spain (2), Switzerland (1) and UK (8). Compared with WE, treatment of HIV and TB in EE are less often located at the same site (47% in EE versus 100% in WE; P < 0.001) and less often provided by the same doctors (41% versus 90%, respectively; P = 0.002), whereas regular screening of HIV‐infected patients for TB (80% versus 40%, respectively; P = 0.037) and directly observed treatment (88% versus 20%, respectively; P < 0.001) were more common in EE. The reported availability of rifabutin and second‐ and third‐line anti‐TB drugs was lower, and opioid substitution therapy (OST) was available at fewer centres in EE compared with WE (53% versus 100%, respectively; P < 0.001). Conclusions: Major differences exist between EE and WE in relation to the organization and delivery of health care for HIV/TB‐coinfected patients and the availability of anti‐TB drugs and OST. Significant discrepancies between reported and actual clinical practices were found in EE

Major Challenges in clinical management of TB/HIV coinfected patients in Eastern Europe compared with Western Europe and Latin America

Objectives: rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in EE, Western Europe (WE) and Latin America (LA). Design and methods: between January 1, 2011, and December 31, 2013, 1413 TB/HIV patients (62 clinics in 19 countries in EE, WE, Southern Europe (SE), and LA) were enrolled. Results: significant differences were observed between EE (N = 844), WE (N = 152), SE (N = 164), and LA (N = 253) in the proportion of patients with a definite TB diagnosis (47%, 71%, 72% and 40%, p<0.0001), MDR-TB (40%, 5%, 3% and 15%, p<0.0001), and use of combination antiretroviral therapy (cART) (17%, 40%, 44% and 35%, p<0.0001). Injecting drug use (adjusted OR (aOR) = 2.03 (95% CI 1.00-4.09), prior anti-TB treatment (3.42 (1.88-6.22)), and living in EE (7.19 (3.28-15.78)) were associated with MDR-TB. Among 585 patients with drug susceptibility test (DST) results, the empiric (i.e. without knowledge of the DST results) anti-TB treatment included ≥3 active drugs in 66% of participants in EE compared with 90-96% in other regions (p<0.0001). Conclusions: in EE, TB/HIV patients were less likely to receive a definite TB diagnosis, more likely to house MDR-TB and commonly received empiric anti-TB treatment with reduced activity. Improved management of TB/HIV patients in EE requires better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART

iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy

Background: HIV therapeutic vaccination aims to improve the immune responses against HIV in order to control viral replication without the need for combined antiretroviral therapy (cART). iHIVARNA-01 is a novel vaccine combining mRNA delivery and T-cell immunogen (HTI) based on conserved targets of effective antiviral T-cell responses. In addition, it holds adequate stimuli required for activating antigen presenting cells (APC)s and co-activating specific T-cells (TriMix), including human CD40L, constitutively active TLR4 (caTLR4) and CD70. We propose that in-vivo targeting of dendritic cells (DCs) by direct administration of a HIV mRNA encoding these immune modulating proteins might be an attractive alternative to target DCs in vitro. Methods/design: This is a phase-IIa, randomized, double-blinded, placebo-controlled, multicenter study in chronically HIV-1 infected patients under stable cART. One of the three study arms is randomly allocated to subjects. Three vaccinations with either HIVACAT T-cell immunogen (HTI)-TriMix (iHIVARNA-01), TriMix or water for injection (WFI) (weeks 0, 2 and 4) are administered by intranodal injection in the inguinal region. Two weeks after the last immunization (week 6) cART is stopped for 12 weeks. The two primary endpoints are: (1) safety and tolerability of intranodal iHIVARNA-01 vaccination compared with TriMix or WFI and (2) induced immunogenicity, i.e., increase in the frequency of HIV-specific T-cell responses between baseline, week 6 and 12 weeks after treatment interruption in iHIVARNA-01-treated patients as compared to the control groups, immunized with TriMix-mRNA or WFI measured by an IFNγ ELISPOT assay. Secondary endpoints include the evaluation of time to viral rebound, plasma viral load (pVL) at w18, the proportion of patients with control of viral load, induction of T-cell responses to new HIV epitopes, polyfunctionality of HIV-specific T-cells, CD8+ T-cell in-vitro HIV suppressive capacity, the effect on viral reservoir (measured by proviral DNA and cell-associated RNA), assessment of viral immune escape by mutation and mRNA expression profiles of host immune genes. Discussion: This trial aims to direct target DC in situ with mRNA encoding HTI and TriMix for co-stimulation. Intranodal injection circumvents laborious DC isolation and handling in the laboratory. The trial extends on the safety results of a phase-I dose-escalating trial. This candidate vaccine could complement or even replace cART for chronic HIV infection and could be applicable to improve the care and cost of HIV infection

Immunological function restoration with Lopinavir/ritonavir vs Efavirenz containing regimens in HIV infected patients: a randomized clinical trial

CD4+ count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function parameters and the relationship with the gain of CD4+ count have not been assessed in a randomized clinical trial. Fifty antiretroviral treatment (cART) naïve HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine for 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, interleukin (IL)-7-receptor/IL-7 system, thymic volume, and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Both groups experienced a CD4+ count increase that was higher in the EFV group (ΔCD4+ 88 vs. 315 cells/μl LPV/r vs. EFV, respectively, p<0.001). Despite this difference in CD4+ gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion, and apoptosis on CD4+ and CD8+ T cells (p<0.001 for all) and a significant increase in markers of thymic function, IL-7 receptor, and in the levels of central memory CD4+ T cells and naive subsets of CD8+ T cells (p<0.001 for all) with respect to baseline values were observed without any difference between groups. These data indicate that the differences in CD4+ gain with different cART regimens are not immunologically meaningful and might explain the similar clinical efficacy of these regimens

Ciencia y profesión : el farmacéutico en la historia

474 páginas. Versiones pdf / epubLas IV Jornadas Científicas de la Sociedad de Docentes Universitarios de Historia de la Farmacia (SDUHFE) se celebraron en la Sede de La Rábida en junio de 2016. Esta obra presenta diversas investigaciones y comunicaciones, con varias temáticas que pueden desglosarse en cuatro bloques: 1) En un primer grupo podemos considerar todos los capítulos que abordan la historia de los colegios farmacéuticos así como los avatares de la profesión. Se da cuenta en la provincia de Sevilla de las dificultades del Colegio de Farmacéuticos en el periodo de la Guerra Civil y la Posguerra (1936-1949), del proceso de colegiación obligatoria a partir de 1916, pinceladas históricas sobre los farmacéuticos cántabros del siglo XIX, del Colegio de Farmacéuticos de Filipinas a finales del XIX, de los conflictos de los farmacéuticos en las reuniones sanitarias de mitad del XX, y del papel de los farmacéuticos titulares en la potabilización de las aguas de consumo en Plentzia (Vizcaya). 2) Podemos destacar también todos los trabajos que giran en torno a diferentes medicamentos y productos farmacéuticos, entre ellos estudios históricos sobre piedras preciosas, medicamentos para tratar heridas, quina contra las tercianas, opio, alexifármacos, medicamentos homeopáticos, talidomida o curiosos productos como el Licor del Polo. 3) El papel de los laboratorios farmacéuticos como la Casa Nestlé durante la Guerra Civil española y el franquismo, diferentes laboratorios onubenses durante este mismo periodo, el papel del Instituto de Higiene Militar y la experimentación con insecticidas clorados sintéticos en la posguerra española, aglutinan el tercer cuerpo temático. 4) Finalmente, podemos destacar los trabajos que tienen una componente publicitaria, divulgadora y social entre los que cabe destacar el estudio del NO-DO y los diferentes noticieros y documentales sobre temas farmacéuticos que resultan muy ilustrativos. La propaganda farmacéutica desarrollada en la revista Matronas, el inventario del patrimonio farmacéutico catalán, junto a la percepción social de la farmacia a través de las fallas valencianas conforma este último grupo

A modular approach to sphingolipid analogs mediated by aziridines: Synthesis and biological studies

El text dels capítols 3, 5, 6 i 7 ha estat retirat seguint instruccions de l’autora de la tesi, en existir participació d’empreses, existir conveni de confidencialitat o existeix la possibilitat de generar patents / El texto delos capítulos 3,5, 6 y 7 ha sido retirado siguiendo instrucciones de la autora, al existir participación de empresas, convenio de confidencialidad o la posibilidad de generar patentes / The text of chapters 3, 5, 6 and 7 has been withdrawn on the instructions of the author, as there is participation of undertakings, confidentiality agreement or the ability to generate patent[eng] Sphingolipids are essential biomolecules for the physiological cell function. In addition to its structural role in cell membranes, these lipids have also crucial functions in signal transduction and cell regulation. As a consequence of the important biological roles of sphingolipids, the synthesis of their analogs and the development of chemical inhibitors of sphingolipid enzymes are the object of current interest. Furthermore, it has been reported that slight modifications on the natural C1 (phyto)sphingosine scaffold or variations in its chain lengths can potentially alter the role and bioactivity of sphingolipid analogs. On the other hand, cyclitols are an important group of compounds due to their remarkable biological activities as well as their synthetic usefulness in the synthesis of other natural compounds or pharmaceuticals. Specially, the development of carbohydrate mimetics prompted primarily by their properties as glycosidase inhibitors, has led to a wide variety of novel structures by themselves or when considering them as key synthetic precursors of more complex molecules such as glycosphingolipids. For the above‐mentioned reasons, we developed a synthetic methodology towards sphingolipid analogs based on the regioselective ring‐opening reactions of N‐acylaziridines with different nucleophiles such as thiols or beta‐glycosil thiols, amines, phosphate derivatives or phosphorothioate derivatives. This approach is a short and flexible route for the synthesis of a variety of (phyto)sphingolipid analogs from aziridine derivatives and this method leads to molecules with different groups bonded to the C‐1 position of the sphingoid backbone from common intermediate aziridines by changing the nucleophile in the ring‐opening reaction step. Moreover, the diversity of compounds obtained is extended by introducing different N‐acyl groups at the nitrogen aziridine. Once, the desired sphingolipid analogs were obtained, a representative selection of them was tested in enzyme assays to identify inhibitors of mammalian sphingolipid metabolism enzymes, such as sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS). Some of the tested analogs were potent inhibitors of GCS and none of them inhibited SMS at concentrations relevant for activity. In general, the inhibitory activity was higher for phytosphingosine analogs than their corresponding sphingosine analogs and the presence of the double bond between C4 and C5 of the sphingosine backbone in analogs was important for their bioactivity, since the dihydroceramide analogs were less active. In addition, a collection of (phyto)sphingolipid analogs were tested in an assay to identify inhibitors against yeast inositol phosphorylceramide synthase (IPCS). Generally, the inhibitory activities were lower than the inhibitions against GCS. However, one analog depicted selectivity against baker’s yeast IPCS since no inhibition of mammalian SMS and GCS was observed. For that reason, this analog showed potential properties as antifungal agent. Some (phyto)sphingolipid analogs were also tested as antigens for CD1d‐restricted iNKT cells and some of them were active, although this activity was lower when comparing with the endogenous glycolipid beta‐glucosylceramide. In particular, the most active compound was a nonglycosidic phytoceramide analog, but some glycosphingolipid analogs were also active in the activation of iNKT cells. However, these compounds were considered weak antigens. Finally, in order to obtain glycolipid analogs a synthetic methodology to obtain enantio‐ and diastereomerically pure galacto‐configured aziridines based on olefin aziridination reactions was examined. This consists in the use of nitrene precursors and a galactose related cyclohexene. The results obtained with this method showed potential for the preparation of the aziridine compounds.[spa] Los esfingolípidos (SL) son biomoléculas esenciales para las funciones fisiológicas de las células. El metabolismo anómalo o la expresión de SL específicos o glicoesfingolípidos (GSL) es el origen de diferentes enfermedades como las esfingolipidosis, causadas por la presencia de mutaciones en las enzimas que intervienen en la biosíntesis de SL o GSL. Debido a la importancia biológica de los SL, el desarrollo de inhibidores químicos de las enzimas que intervienen en el metabolismo de los SL de mamíferos y hongos, es un tema de gran interés científico. Por otro lado, cabe remarcar que los ciclitoles son un tipo de compuestos muy interesantes debido a su remarcable actividad biológica y a su utilidad como precursores sintéticos de moléculas más complejas como los GSL. Teniendo en cuenta las consideraciones comentadas anteriormente, se ha desarrollado una nueva metodología sintética para la obtención de análogos de SLs basada en las reacciones de apertura de Nacilaziridinas con diferentes nucleófilos como tioles, beta‐glicosil tioles, aminas, fosfatos y fosforotioatos. Esta aproximación es una ruta corta y flexible para la obtención de análogos lipídicos con diversidad estructural. Una selección representativa de los compuestos sintetizados se ensayó frente a la inhibición de enzimas del metabolismo de los mamíferos tales como la esfingomielin sintasa (SMS) y la glucosilceramida sintasa (GCS), y enzimas del metabolismo de los hongos como la inositol fosforilceramida sintasa (IPCS). Algunos de estos análogos resultaron ser inhibidores potentes de la GCS pero ninguno de ellos fue inhibidor de la SMS. Mientras que la inhibición frente a la IPCS en levaduras fue más baja en comparación con la inhibición de la GCS. A pesar de ello, uno de los análogos ensayados mostró selectividad frente a la IPCS ya que no se observó inhibición de la SMS y la GCS de mamíferos, mostrando así propiedades interesantes como agente antifúngico. De manera adicional, algunos análogos de (fito)esfingolípidos fueron ensayados como antígenos de células iNKT restringidas por la proteína CD1d y resultaron activos. Curiosamente, el compuesto más activo resultó ser un análogo de fitoceramida no glicosídico, aunque otros GSL también resultaron activos. Por otro lado, se desarrolló una metodología sintética para obtener aziridinas con configuración galacto (análogos de galactosa) enantiomericamente y diastereomericamente puras para obtener análogos de glicolípidos

Aziridine ring opening for the synthesis of sphingolipid analogues: Inhibitors of sphingolipid-metabolizing enzymes

A library of sphingolipid analogues is designed and tested as inhibitors against mammalian and fungal sphingolipid enzymes. The synthesis of sphingolipid analogues is based on the nucleophilic ring-opening reactions of N-activated aziridine derivatives with thiols, β-thioglycosyl thiols, phosphorothioates, phosphates, and amines to afford compounds having different lipid backbones and substituents representative of the naturally occurring sphingolipid families. The screening on mammalian sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS) and yeast inositol phosphorylceramide synthase (IPCS) enzymes identified several inhibitors of GCS and IPCS, but no inhibition of SMS was observed among the tested compounds. © 2014 American Chemical Society.Peer Reviewe