[Essential oils, a response to unpleasant odors in resuscitation of burn victims]. / Les huiles essentielles, une réponse aux ressentis d'odeurs désagréables en réanimation des grands brûlés.

In burn units, odor is often underestimated or trivialized in relation to the critical context of the patients. However, their care is part of a concern for overall care, which also includes the caregiver and the visitor. The implementation of a project based on essential oils has allowed a team from the University Hospital of Toulouse to address this issue.

Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors.

Strokes remain one of the leading causes of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity. Calcium-permeable AMPA receptors (AMPARs), lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C kinase-1 (PICK1). The purpose of the present study is to evaluate whether treatment with a PICK1 inhibitor, FSC231, prevents the OGD/R-induced degradation of the GluA2 AMPAR subunit. Utilizing an acute rodent hippocampal slice model system, we determined that pretreatment with FSC231 prevented the OGD/R-induced association of PICK1-GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This suggests that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels.

Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase.

Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors toward CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed. Here the synthesis and potent inhibitory activity of the first CYP26A1 selective inhibitors is reported. A series of nonazole CYP26A1 selective inhibitors was identified with low nM potency. The lead compound 3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl] phenyl}4-propanoic acid (24) had 43-fold selectivity toward CYP26A1 with an IC50 of 340 nM. Compound 24 and its two structural analogues also inhibited atRA metabolism in HepG2 cells, resulting in increased potency of atRA toward RAR activation. The identified compounds have potential to become novel treatments aiming to elevate endogenous atRA concentrations and may be useful as cotreatment with atRA to combat therapy resistance.

Identification of NADPH oxidase as a key mediator in the post-ischemia-induced sequestration and degradation of the GluA2 AMPA receptor subunit.

A hallmark of ischemic/reperfusion injury is a change in subunit composition of synaptic 2-amino-3-(3-hydroxy-5-methylisoazol-4-yl)propionic acid receptors (AMPARs). This change in AMPAR subunit composition leads to an increase in surface expression of GluA2-lacking Ca(2+) /Zn(2+) permeable AMPARs. These GluA2-lacking AMPARs play a key role in promoting delayed neuronal death following ischemic injury. At present, the mechanism(s) responsible for the ischemia/reperfusion-induced subunit composition switch and degradation of the GluA2 subunit remain unclear. In this study, we investigated the role of NADPH oxidase, and its importance in mediating endocytosis and subsequent degradation of the GluA2 AMPAR subunit in adult rat hippocampal slices subjected to oxygen-glucose deprivation/reperfusion (OGD/R) injury. In hippocampal slices pre-treated with the NADPH oxidase inhibitor apocynin attenuated OGD/R-mediated sequestration of GluA2 and GluA1 as well as prevent the degradation of GluA2. We provide compelling evidence that NADPH oxidase mediated sequestration of GluA1- and GluA2- involved activation of p38 MAPK. Furthermore, we demonstrate that inhibition of NADPH oxidase blunts the OGD/R-induced association of GluA2 with protein interacting with C kinase-1. In summary, this study identifies a novel mechanism that may underlie the ischemia/reperfusion-induced AMPAR subunit composition switch and a potential therapeutic target.

Mastering tricyclic ring systems for desirable functional cannabinoid activity.

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. Functional activity and selectivity at human CB1 and CB2 receptors were characterized using receptor internalization and [(35)S]GTP-γ-S assays. The structure-activity relationship and optimization studies of the carbazole series have led to the discovery of a non-selective CB1 and CB2 agonist, compound 4. Our subsequent research efforts to increase CB2 selectivity of this lead compound have led to the discovery of CB2 selective compound 64, which robustly internalized CB2 receptors. Compound 64 had potent inhibitory effects on pain hypersensitivity in a rat model of neuropathic pain. Other potent and CB2 receptor-selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment.

In vivo efficacy of enabling formulations based on hydroxypropyl-ß-cyclodextrins, micellar preparation, and liposomes for the lipophilic cannabinoid CB2 agonist, MDA7.

Enabling formulations based on hydroxypropyl-ß-cyclodextrins (HPßCD), micellar preparation, and liposomes have been designed to deliver the racemic mixture of a lipophilic cannabinoid type 2 agonist, MDA7. The antiallodynic effects of MDA7 formulated in these three different systems were compared after intravenous (i.v.) administration in rats. Stoichiometry of the inclusion complex formed by MDA7 in HPßCD was determined by continuous variation plot, electrospray ionization-mass spectrometry (ESI-MS) analysis, phase solubility, and nuclear magnetic resonance studies and indicate formation of exclusively 1:1 adduct. Morphology and particle sizes determined by dynamic light scattering and transmission electron microscopy show the presence of a homogeneous population of closed round-shaped oligolamellar MDA7 containing liposomes, with an average size of 118 nm [polydispersity index (PDI) 0.03]. Monodisperse micelles exhibited an average size of 14 nm (PDI 0.09). HPßCD-based formulation administrated in vivo was composed of two discrete particles populations with a narrow size distribution of 3 nm (PDI 0.04) and 510 nm (PDI 0.02). HPßCD-based formulation dramatically improved antiallodynic effect of MDA7 in comparison with the liposomes preparation. Through inclusion complexation and possibly formation of aggregates, HPßCD can enhance the aqueous solubility of lipophilic drugs, thereby improving their bioavailability for i.v. administration.

Pharmacological characterization of a novel cannabinoid ligand, MDA19, for treatment of neuropathic pain.

BACKGROUND: Cannabinoid receptor 2 (CB2) agonists have recently gained attention as potential therapeutic targets in the management of neuropathic pain. In this study, we characterized the pharmacological profile of the novel compound N'-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]benzohydrazide (MDA19), a CB2 agonist. METHODS: We used radioligand binding assays and multiple in vitro functional assays at human and rat CB(1) and CB(2) receptors. The effects of MDA19 in reversing neuropathic pain were assessed in various neuropathic pain models in rats and in CB2(+/+) and CB2(-/-) mice. RESULTS: MDA19 displayed 4-fold-higher affinity at the human CB(2) than at the human CB1 receptor (K(i) = 43.3 +/- 10.3 vs 162.4 +/- 7.6 nM) and nearly 70-fold-higher affinity at the rat CB2 than at the rat CB1 receptor (K(i) = 16.3 +/- 2.1 vs 1130 +/- 574 nM). In guanosine triphosphate (GTP)gamma[(35)S] functional assays, MDA19 behaved as an agonist at the human CB1 and CB2 receptors and at the rat CB1 receptor but as an inverse agonist at the rat CB2 receptor. In 3',5'-cyclic adenosine monophosphate (cAMP) assays, MDA19 behaved as an agonist at the rat CB1 receptor and exhibited no functional activity at the rat CB(2) receptor. In extracellular signal-regulated kinases 1 and 2 activation assays, MDA19 behaved as an agonist at the rat CB2 receptor. MDA19 attenuated tactile allodynia produced by spinal nerve ligation or paclitaxel in a dose-related manner in rats and CB2(+/+) mice but not in CB2(-/-) mice, indicating that CB2 receptors mediated the effects of MDA19. MDA19 did not affect rat locomotor activity. CONCLUSIONS: We found that MDA19 exhibited a distinctive in vitro functional profile at rat CB2 receptors and behaved as a CB1/CB2 agonist in vivo, characteristics of a protean agonist. MDA19 has potential for alleviating neuropathic pain without producing adverse effects in the central nervous system.

2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists: design, synthesis, and binding mode prediction through ligand-steered modeling.

We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB(2)) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB(2) agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 (compound 19) and MDA39 (compound 30) were the most potent at CB(2). MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.

6-Methoxy-N-alkyl isatin acylhydrazone derivatives as a novel series of potent selective cannabinoid receptor 2 inverse agonists: design, synthesis, and binding mode prediction.

Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC(50) = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (K(i) = 89.9 nM, EC(50) = 88.2 nM at CB2) inhibited the effect of compound 1 (MDA7), a selective CB2 agonist, in an animal model of neuropathic pain. The molecular modeling study presented here represents a first study of CB2 based on the structure of beta(2)-adrenergic receptor. A ligand-based homology model of the CB2 binding site was developed, and on the basis of our results, we propose a general binding mode for this class of inverse agonists with CB2.

Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of neuropathic pain.

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [(35)S]GTP-gamma-S assays. Binding affinities at human CB2 and CB1 were determined for compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.

Mortalidad fetal, frecuencia y factores de riesgo, Departamento de Antioquia, Noviembre de 1997 a junio de 1998 / Fetal mortality: frequency and risk factors: Antioquia state, November 1997 to June 1998

Utilizando las bases de datos del Departamento Administrativo Nacional de Estadística (DANE) de nacimiento y defunciones para Antioquia entre Noviembre de 1997 y Junio de 1998, se realizo un estudio en dos etapas, una descriptiva utilizando el total de la población y otra de casos y controles, con una muestra de 305 casos y 305 controles. Se encontró una tasa de mortalidad fetal para el Departamento de 39.16 x 1000 nacidos vivos (n.v,), en el área urbana fue mayor la tasa de mortalidad (44.47 x 1000 n.v.), la mayor parte de las muertes fatales sucedieron en la 20 primeras semanas de gestión (66.72 por ciento). Con el análisis de casos y controles y de regresión logística se halló: al numero de hijos nacidos muertos “al menos uno” como potente factor predictivo (RD 44.13 IC95 por ciento (26.76-73.17)). Coeficiente de Correlación de 0.4521, otras características fueron la edad de la madre “mayor de 40 años” encontrándose una asociación con la muerte fetal (RD 2094 IC (1.04-8.26)), pero con el análisis multivariado se vio que esta asociación estaba afectada por la confusión del área de resistencia, igual sucedió con el estado civil soltera otras variables como la edad menor a 20 años, el nivel educativo bajo, el número de embarazos mayor a cuatro no están asociados a la muerte fetal, aunque se encontraron con altas tasas de mortalidad fetal.

Mesotelioma maligno peritoneal en un jóven sin factores de riesgo: informe de un caso

Se informa el caso de un hombre de 21 años de edad, natural y procedente de Bogotá, ayudante de conductor, quien fue remitido al Hospital Regional Simón Bolívar por cuadro de un mes de evolución consistente en pérdida de peso, febrícula, distención abdominal y desde ocho días antes del ingreso, estreñimiento. Al examen físico se encontró ascitis, acompañada de circulación colateral. El liquido ascítico era de aspecto hemorrágico y el citoquímico compatible con exudado. La ecografía abdominal reportó engrosamiento difuso del peritoneo. En la escanografía abdominal se observó una masa de densidad heterogénea que ocupaba la totalidad de la cavidad, comprometiendo espacios extra e intramesentéricos. Biopsias por punción fueron compatibles con sarcoma mal diferenciado, el estudio histopatológico del tejido posible de resecar durante la cirugía fue concluyente de mesotelioma maligno. No se identificaron factores de riesgo para el desarrollo de este tipo de neoplasia

Estudio exploratorio de 100 pacientes farmacodependientes patrones de consumo, multicausalidad, personalidad y otros diagnósticos asociados / Exploratory study of 100 pharmacodependent patients: consumption patrons, mulcasuality, personality and other associated diagnostic

Se estudió una muestra de 100 (Ss) fármacodependientes que consultaron el Ambulatorio de San Bernardino de la Fundación José Felix Ribas para determinar las drogas utilizadas, el patrón de consumo, factores etiológicos, rasgos de personalidad y entidades psiquiátricas asociadas. Para ello se desarrolló un instrumento de 102 items. Se apareció que la mayoría fueron jóvenes varones menores de 26 años, con bajo nivel educacional, inestables laboralmente, con dificultades para mantener vínculos. La droga de inicio fue la Marihuana especialmente antes de los 16 años y las más usadas actualmente fueron en orden de frecuencia: Bazuco, Marihuana, Cocaina, Alcohol; predominando el uso mixto. Etiológicamente los factores resaltantes se ubicaron en experiencias de la infancia, fijaciones del desarrollo psicomotriz, desestructuración familiar y otros de tipo psicológico. En un 35%se hicieron otros diagnósticos concomitantes del axis I y 74%de transtornos de personalidad, especialmente antisocial, dependiente y borderline